The Drosophila HEM-2/NAP1 homolog KETTE controls axonal pathfinding and cytoskeletal organization

PubMed Central

Hummel, Thomas; Leifker, Karin; Klämbt, Christian

2000-01-01

In Drosophila, the correct formation of the segmental commissures depends on neuron–glial interactions at the midline. The VUM midline neurons extend axons along which glial cells migrate in between anterior and posterior commissures. Here, we show that the gene kette is required for the normal projection of the VUM axons and subsequently disrupts glial migration. Axonal projection defects are also found for many other moto- and interneurons. In addition, kette affects the cell morphology of mesodermal and epidermal derivatives, which show an abnormal actin cytoskeleton. The KETTE protein is homologous to the transmembrane protein HEM-2/NAP1 evolutionary conserved from worms to vertebrates. In vitro analysis has shown a specific interaction of the vertebrate HEM-2/NAP1 with the SH2–SH3 adapter protein NCK and the small GTPase RAC1, which both have been implicated in regulating cytoskeleton organization and axonal growth. Hypomorphic kette mutations lead to axonal defects similar to mutations in the Drosophila NCK homolog dreadlocks. Furthermore, we show that kette and dock mutants genetically interact. NCK is thought to interact with the small G proteins RAC1 and CDC42, which play a role in axonal growth. In line with these observations, a kette phenocopy can be obtained following directed expression of mutant DCDC42 or DRAC1 in the CNS midline. In addition, the kette mutant phenotype can be partially rescued by expression of an activated DRAC1 transgene. Our data suggest an important role of the HEM-2 protein in cytoskeletal organization during axonal pathfinding. PMID:10766742

Flamingo, a seven-pass transmembrane cadherin, cooperates with Netrin/Frazzled in Drosophila midline guidance.

PubMed

Organisti, Cristina; Hein, Irina; Grunwald Kadow, Ilona C; Suzuki, Takashi

2015-01-01

During central nervous system development, several guidance cues and receptors, as well as cell adhesion molecules, are required for guiding axons across the midline and along the anterior-posterior axis. In Drosophila, commissural axons sense the midline attractants Netrin A and B (Net) through Frazzled (Fra) receptors. Despite their importance, lack of Net or fra affects only some commissures, suggesting that additional molecules can fulfill this function. Recently, planar cell polarity (PCP) proteins have been implicated in midline axon guidance in both vertebrate and invertebrate systems. Here, we report that the atypical cadherin and PCP molecule Flamingo/Starry night (Fmi/Stan) acts jointly with Net/Fra signaling during midline development. Additional removal of fmi strongly increases the guidance defects in Net/fra mutants. Rescue and domain deletion experiments suggest that Fmi signaling facilitates commissural pathfinding potentially by mediating axonal fasciculation in a partly homophilic manner. Altogether, our results indicate that contact-mediated cell adhesion via Fmi acts in addition to the Net/Fra guidance system during axon pathfinding across the midline, underlining the importance of PCP molecules during vertebrates and invertebrates midline development. © 2014 The Authors Genes to Cells © 2014 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

A cascade of morphogenic signaling initiated by the meninges controls corpus callosum formation.

PubMed

Choe, Youngshik; Siegenthaler, Julie A; Pleasure, Samuel J

2012-02-23

The corpus callosum is the most prominent commissural connection between the cortical hemispheres, and numerous neurodevelopmental disorders are associated with callosal agenesis. By using mice either with meningeal overgrowth or selective loss of meninges, we have identified a cascade of morphogenic signals initiated by the meninges that regulates corpus callosum development. The meninges produce BMP7, an inhibitor of callosal axon outgrowth. This activity is overcome by the induction of expression of Wnt3 by the callosal pathfinding neurons, which antagonize the inhibitory effects of BMP7. Wnt3 expression in the cingulate callosal pathfinding axons is developmentally regulated by another BMP family member, GDF5, which is produced by the adjacent Cajal-Retzius neurons and turns on before outgrowth of the callosal axons. The effects of GDF5 are in turn under the control of a soluble GDF5 inhibitor, Dan, made by the meninges. Thus, the meninges and medial neocortex use a cascade of signals to regulate corpus callosum development. Copyright © 2012 Elsevier Inc. All rights reserved.

A cascade of morphogenic signaling initiated by the meninges controls corpus callosum formation

PubMed Central

Choe, Youngshik; Siegenthaler, Julie A.; Pleasure, Samuel J.

2012-01-01

Summary The corpus callosum is the most prominent commissural connection between the cortical hemispheres, and numerous neurodevelopmental disorders are associated with callosal agenesis. Using mice with either meningeal overgrowth or selective loss of meninges, we’ve identified a cascade of morphogenic signals initiated by the meninges that regulates corpus callosum development. The meninges produce BMP7, an inhibitor of callosal axon outgrowth. This activity is overcome by the induction of expression of Wnt3 by the callosal pathfinding neurons, which antagonizes the inhibitory effects of BMP7. Wnt3 expression in the cingulate callosal pathfinding axons is developmentally regulated by another BMP family member, GDF5, produced by the adjacent Cajal-Retzius neurons and turns on before outgrowth of the callosal axons. The effects of GDF5 are in turn under the control of a soluble GDF5 inhibitor, Dan, made by the meninges. Thus, the meninges and medial neocortex use a cascade of signals to regulate corpus callosum development. PMID:22365545

Drosophila as a genetic and cellular model for studies on axonal growth

PubMed Central

Sánchez-Soriano, Natalia; Tear, Guy; Whitington, Paul; Prokop, Andreas

2007-01-01

One of the most fascinating processes during nervous system development is the establishment of stereotypic neuronal networks. An essential step in this process is the outgrowth and precise navigation (pathfinding) of axons and dendrites towards their synaptic partner cells. This phenomenon was first described more than a century ago and, over the past decades, increasing insights have been gained into the cellular and molecular mechanisms regulating neuronal growth and navigation. Progress in this area has been greatly assisted by the use of simple and genetically tractable invertebrate model systems, such as the fruit fly Drosophila melanogaster. This review is dedicated to Drosophila as a genetic and cellular model to study axonal growth and demonstrates how it can and has been used for this research. We describe the various cellular systems of Drosophila used for such studies, insights into axonal growth cones and their cytoskeletal dynamics, and summarise identified molecular signalling pathways required for growth cone navigation, with particular focus on pathfinding decisions in the ventral nerve cord of Drosophila embryos. These Drosophila-specific aspects are viewed in the general context of our current knowledge about neuronal growth. PMID:17475018

Pathfinding in a large vertebrate axon tract: isotypic interactions guide retinotectal axons at multiple choice points

PubMed Central

Pittman, Andrew J.; Law, Mei-Yee; Chien, Chi-Bin

2008-01-01

Summary Navigating axons respond to environmental guidance signals, but can also follow axons that have gone before—pioneer axons. Pioneers have been studied extensively in simple systems, but the role of axon-axon interactions remains largely unexplored in large vertebrate axon tracts, where cohorts of identical axons could potentially use isotypic interactions to guide each other through multiple choice points. Furthermore, the relative importance of axon-axon interactions compared to axon-autonomous receptor function has not been assessed. Here we test the role of axon-axon interactions in retinotectal development, by devising a technique to selectively remove or replace early-born retinal ganglion cells (RGCs). We find that early RGCs are both necessary and sufficient for later axons to exit the eye. Furthermore, introducing misrouted axons by transplantation reveals that guidance from eye to tectum relies heavily on interactions between axons, including both pioneer-follower and community effects. We conclude that axon-axon interactions and ligand-receptor signaling have coequal roles, cooperating to ensure the fidelity of axon guidance in developing vertebrate tracts. PMID:18653554

How does calcium interact with the cytoskeleton to regulate growth cone motility during axon pathfinding?

PubMed

Gasperini, Robert J; Pavez, Macarena; Thompson, Adrian C; Mitchell, Camilla B; Hardy, Holly; Young, Kaylene M; Chilton, John K; Foa, Lisa

2017-10-01

The precision with which neurons form connections is crucial for the normal development and function of the nervous system. The development of neuronal circuitry in the nervous system is accomplished by axon pathfinding: a process where growth cones guide axons through the embryonic environment to connect with their appropriate synaptic partners to form functional circuits. Despite intense efforts over many years to understand how this process is regulated, the complete repertoire of molecular mechanisms that govern the growth cone cytoskeleton and hence motility, remain unresolved. A central tenet in the axon guidance field is that calcium signals regulate growth cone behaviours such as extension, turning and pausing by regulating rearrangements of the growth cone cytoskeleton. Here, we provide evidence that not only the amplitude of a calcium signal is critical for growth cone motility but also the source of calcium mobilisation. We provide an example of this idea by demonstrating that manipulation of calcium signalling via L-type voltage gated calcium channels can perturb sensory neuron motility towards a source of netrin-1. Understanding how calcium signals can be transduced to initiate cytoskeletal changes represents a significant gap in our current knowledge of the mechanisms that govern axon guidance, and consequently the formation of functional neural circuits in the developing nervous system. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Floor plate chemoattracts crossed axons and chemorepels uncrossed axons in the vertebrate brain.

PubMed

Tamada, A; Shirasaki, R; Murakami, F

1995-05-01

In the bilaterally symmetrical vertebrate CNS, all developing axons must choose between remaining on the same side of the midline or growing across it. The mechanism underlying this axonal pathfinding is, however, poorly understood. Here we demonstrate that the ventral midline floor plate (FP) chemorepels two types of ipsilaterally projecting axons, one from the alar plate and another from the basal plate in the mesencephalon. We further demonstrate that the FP chemoattracts contralaterally projecting myelencephalic as well as metencephalic axons. The FP at all axial levels displayed both chemoattractive and chemorepellent activities, suggesting that FP chemoattraction and chemorepulsion may be at work throughout the neuraxis. Chemotropic guidance by the FP may therefore play a key role in the establishment of neuronal projection laterality.

Slow Muscle Precursors Lay Down a Collagen XV Matrix Fingerprint to Guide Motor Axon Navigation.

PubMed

Guillon, Emilie; Bretaud, Sandrine; Ruggiero, Florence

2016-03-02

The extracellular matrix (ECM) provides local positional information to guide motoneuron axons toward their muscle target. Collagen XV is a basement membrane component mainly expressed in skeletal muscle. We have identified two zebrafish paralogs of the human COL15A1 gene, col15a1a and col15a1b, which display distinct expression patterns. Here we show that col15a1b is expressed and deposited in the motor path ECM by slow muscle precursors also called adaxial cells. We further demonstrate that collagen XV-B deposition is both temporally and spatially regulated before motor axon extension from the spinal cord in such a way that it remains in this region after the adaxial cells have migrated toward the periphery of the myotome. Loss- and gain-of-function experiments in zebrafish embryos demonstrate that col15a1b expression and subsequent collagen XV-B deposition and organization in the motor path ECM depend on a previously undescribed two-step mechanism involving Hedgehog/Gli and unplugged/MuSK signaling pathways. In silico analysis predicts a putative Gli binding site in the col15a1b proximal promoter. Using col15a1b promoter-reporter constructs, we demonstrate that col15a1b participates in the slow muscle genetic program as a direct target of Hedgehog/Gli signaling. Loss and gain of col15a1b function provoke pathfinding errors in primary and secondary motoneuron axons both at and beyond the choice point where axon pathway selection takes place. These defects result in muscle atrophy and compromised swimming behavior, a phenotype partially rescued by injection of a smyhc1:col15a1b construct. These reveal an unexpected and novel role for collagen XV in motor axon pathfinding and neuromuscular development. In addition to the archetypal axon guidance cues, the extracellular matrix provides local information that guides motor axons from the spinal cord to their muscle targets. Many of the proteins involved are unknown. Using the zebrafish model, we identified an unexpected role of the extracellular matrix collagen XV in motor axon pathfinding. We show that the synthesis of collagen XV-B by slow muscle precursors and its deposition in the common motor path are dependent on a novel two-step mechanism that determines axon decisions at a choice point during motor axonogenesis. Zebrafish and humans use common molecular cues and regulatory mechanisms for the neuromuscular system development. And as such, our study reveals COL15A1 as a candidate gene for orphan neuromuscular disorders. Copyright © 2016 the authors 0270-6474/16/362663-14$15.00/0.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans.

PubMed

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma.

Multiple cytoskeletal pathways and PI3K signaling mediate CDC-42-induced neuronal protrusion in C. elegans

PubMed Central

Alan, Jamie K; Struckhoff, Eric C; Lundquist, Erik A

2013-01-01

Rho GTPases are key regulators of cellular protrusion and are involved in many developmental events including axon guidance during nervous system development. Rho GTPase pathways display functional redundancy in developmental events, including axon guidance. Therefore, their roles can often be masked when using simple loss-of-function genetic approaches. As a complement to loss-of-function genetics, we constructed a constitutively activated CDC-42(G12V) expressed in C. elegans neurons. CDC-42(G12V) drove the formation of ectopic lamellipodial and filopodial protrusions in the PDE neurons, which resembled protrusions normally found on migrating growth cones of axons. We then used a candidate gene approach to identify molecules that mediate CDC-42(G12V)-induced ectopic protrusions by determining if loss of function of the genes could suppress CDC-42(G12V). Using this approach, we identified 3 cytoskeletal pathways previously implicated in axon guidance, the Arp2/3 complex, UNC-115/abLIM, and UNC-43/Ena. We also identified the Nck-interacting kinase MIG-15/NIK and p21-activated kinases (PAKs), also implicated in axon guidance. Finally, PI3K signaling was required, specifically the Rictor/mTORC2 branch but not the mTORC1 branch that has been implicated in other aspects of PI3K signaling including stress and aging. Our results indicate that multiple pathways can mediate CDC-42-induced neuronal protrusions that might be relevant to growth cone protrusions during axon pathfinding. Each of these pathways involves Rac GTPases, which might serve to integrate the pathways and coordinate the multiple CDC-42 pathways. These pathways might be relevant to developmental events such as axon pathfinding as well as disease states such as metastatic melanoma. PMID:24149939

The C. elegans histone deacetylase HDA-1 is required for cell migration and axon pathfinding.

PubMed

Zinovyeva, Anna Y; Graham, Serena M; Cloud, Veronica J; Forrester, Wayne C

2006-01-01

Histone proteins play integral roles in chromatin structure and function. Histones are subject to several types of posttranslational modifications, including acetylation, which can produce transcriptional activation. The converse, histone deacetylation, is mediated by histone deacetylases (HDACs) and often is associated with transcriptional silencing. We identified a new mutation, cw2, in the Caenorhabditis elegans hda-1 gene, which encodes a histone deacetylase. Previous studies showed that a mutation in hda-1, e1795, or reduction of hda-1 RNA by RNAi causes defective vulval and gonadal development leading to sterility. The hda-1(cw2) mutation causes defective vulval development and reduced fertility, like hda-1(e1795), albeit with reduced severity. Unlike the previously reported hda-1 mutation, hda-1(cw2) mutants are viable as homozygotes, although many die as embryos or larvae, and are severely uncoordinated. Strikingly, in hda-1(cw2) mutants, axon pathfinding is defective; specific axons often appear to wander randomly or migrate in the wrong direction. In addition, the long range migrations of three neuron types and fasciculation of the ventral nerve cord are defective. Together, our studies define a new role for HDA-1 in nervous system development, and provide the first evidence for HDAC function in regulating neuronal axon guidance.

A photon-driven micromotor can direct nerve fibre growth

NASA Astrophysics Data System (ADS)

Wu, Tao; Nieminen, Timo A.; Mohanty, Samarendra; Miotke, Jill; Meyer, Ronald L.; Rubinsztein-Dunlop, Halina; Berns, Michael W.

2012-01-01

Axonal path-finding is important in the development of the nervous system, nerve repair and nerve regeneration. The behaviour of the growth cone at the tip of the growing axon determines the direction of axonal growth and migration. We have developed an optical-based system to control the direction of growth of individual axons (nerve fibres) using laser-driven spinning birefringent spheres. One or two optical traps position birefringent beads adjacent to growth cones of cultured goldfish retinal ganglion cell axons. Circularly polarized light with angular momentum causes the trapped bead to spin. This creates a localized microfluidic flow generating an estimated 0.17 pN shear force against the growth cone that turns in response to the shear. The direction of axonal growth can be precisely manipulated by changing the rotation direction and position of this optically driven micromotor. A physical model estimating the shear force density on the axon is described.

Hypoglossal-facial anastomosis (HFA) over a 10 mm gap bridged by a Y-tube-conduit enhances neurite regrowth and reduces collateral axonal branching at the lesion site.

PubMed

Ozsoy, Umut; Demirel, Bahadir Murat; Hizay, Arzu; Ozsoy, Ozlem; Ankerne, Janina; Angelova, Srebrina; Sarikcioglu, Levent; Ucar, Yasar; Angelov, Doychin N

2011-01-01

The outcome of severe peripheral nerve injuries requiring surgical repair (transection and suture) is usually poor. Recent work suggests that direct suture of nerves increases collagen production and provides unfavourable conditions for a proper axonal regrowth. We tested whether entubulation of the hypoglossal nerve into a Y-tube conduit connecting it with the zygomatic and buccal facial nerve branches would improve axonal pathfinding at the lesion site, quality of muscle reinnervation and recovery of vibrissal whisking. For hypoglossal-facial anastomosis (HFA) over a Y-tube (HFA-Y-tube) the proximal stump of the hypoglossal nerve was entubulated and sutured into the long arm of a Y-tube (isogeneic abdominal aorta with its bifurcation). The zygomatic and buccal facial branches were entubulated and sutured to the short arms of the Y-tube. Restoration of vibrissal motor performance, degree of collateral axonal branching at the lesion site and quality of neuro-muscular junction (NMJ) reinnervation were compared to animals receiving HFA-Coaptation (no entubulation) after 4 months. HFA-Y-tube reduced collateral axonal branching. However it failed to reduce the proportion of polyinnervated NMJ and did not improve functional outcome when compared to HFA-Coaptation. Elimination of compression by tightly opposed nerve fragments improved axonal pathfinding. However, biometric analysis of vibrissae movements did not show positive effects suggesting that polyneuronal reinnervation - rather than collateral branching - may be the critical limiting factor. Since polyinnervation of muscle fibers is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies after HFA could be soon designed and tested.

Axon growth regulation by a bistable molecular switch.

PubMed

Padmanabhan, Pranesh; Goodhill, Geoffrey J

2018-04-25

For the brain to function properly, its neurons must make the right connections during neural development. A key aspect of this process is the tight regulation of axon growth as axons navigate towards their targets. Neuronal growth cones at the tips of developing axons switch between growth and paused states during axonal pathfinding, and this switching behaviour determines the heterogeneous axon growth rates observed during brain development. The mechanisms controlling this switching behaviour, however, remain largely unknown. Here, using mathematical modelling, we predict that the molecular interaction network involved in axon growth can exhibit bistability, with one state representing a fast-growing growth cone state and the other a paused growth cone state. Owing to stochastic effects, even in an unchanging environment, model growth cones reversibly switch between growth and paused states. Our model further predicts that environmental signals could regulate axon growth rate by controlling the rates of switching between the two states. Our study presents a new conceptual understanding of growth cone switching behaviour, and suggests that axon guidance may be controlled by both cell-extrinsic factors and cell-intrinsic growth regulatory mechanisms. © 2018 The Author(s).

Neural guidance molecules regulate vascular remodeling and vessel navigation.

PubMed

Eichmann, Anne; Makinen, Taija; Alitalo, Kari

2005-05-01

The development of the embryonic blood vascular and lymphatic systems requires the coordinated action of several transcription factors and growth factors that target endothelial and periendothelial cells. However, according to recent studies, the precise "wiring" of the vascular system does not occur without an ordered series of guidance decisions involving several molecules initially discovered for axons in the nervous system, including ephrins, netrins, slits, and semaphorins. Here, we summarize the new advances in our understanding of the roles of these axonal pathfinding molecules in vascular remodeling and vessel guidance, indicating that neuronal axons and vessel sprouts use common molecular mechanisms for navigation in the body.

Chondroitinase C Selectively Degrades Chondroitin Sulfate Glycosaminoglycans that Inhibit Axonal Growth within the Endoneurium of Peripheral Nerve.

PubMed

Graham, James B; Muir, David

2016-01-01

The success of peripheral nerve regeneration is highly dependent on the regrowth of axons within the endoneurial basal lamina tubes that promote target-oriented pathfinding and appropriate reinnervation. Restoration of nerve continuity at this structural level after nerve transection injury by direct repair and nerve grafting remains a major surgical challenge. Recently, biological approaches that alter the balance of growth inhibitors and promoters in nerve have shown promise to improve appropriate axonal regeneration and recovery of peripheral nerve function. Chondroitin sulfate proteoglycans (CSPGs) are known inhibitors of axonal growth. This growth inhibition is mainly associated with a CSPG's glycosaminoglycan chains. Enzymatic degradation of these chains with chondroitinase eliminates this inhibitory activity and, when applied in vivo, can improve the outcome of nerve repair. To date, these encouraging findings were obtained with chondroitinase ABC (a pan-specific chondroitinase). The aim of this study was to examine the distribution of CSPG subtypes in rodent, rabbit, and human peripheral nerve and to test more selective biological enzymatic approaches to improve appropriate axonal growth within the endoneurium and minimize aberrant growth. Here we provide evidence that the endoneurium, but not the surrounding epineurium, is rich in CSPGs that have glycosaminoglycan chains readily degraded by chondroitinase C. Biochemical studies indicate that chondroitinase C has degradation specificity for 6-sulfated glycosaminoglycans found in peripheral nerve. We found that chondroitinase C degrades and inactivates inhibitory CSPGs within the endoneurium but not so much in the surrounding nerve compartments. Cryoculture bioassays (neurons grown on tissue sections) show that chondroitinase C selectively and significantly enhanced neuritic growth associated with the endoneurial basal laminae without changing growth-inhibiting properties of the surrounding epineurium. Interestingly, chondroitinase ABC treatment increased greatly the growth-promoting properties of the epineurial tissue whereas chondroitinase C had little effect. Our evidence indicates that chondroitinase C effectively degrades and inactivates inhibitory CSPGs present in the endoneurial Schwann cell basal lamina and does so more specifically than chondroitinase ABC. These findings are discussed in the context of improving nerve repair and regeneration and the growth-promoting properties of processed nerve allografts.

Reciprocal interactions between neurons and glia are required for Drosophila peripheral nervous system development.

PubMed

Sepp, Katharine J; Auld, Vanessa J

2003-09-10

A major developmental role of peripheral glia is to mediate sensory axon guidance; however, it is not known whether sensory neurons influence peripheral glial development. To determine whether glia and neurons reciprocally interact during embryonic development, we ablated each cell type by overexpressing the apoptosis gene, grim, and observed the effects on peripheral nervous system (PNS) development. When neurons are ablated, glial defects occur as a secondary effect, and vice versa. Therefore glia and neurons are codependent during embryogenesis. To further explore glial-neuronal interactions, we genetically disrupted glial migration or differentiation and observed the secondary effects on sensory neuron development. Glial migration and ensheathment of PNS axons was blocked by overexpression of activated Rho GTPase, a regulator of actin dynamics. Here, sensory axons extended to the CNS without exhibiting gross pathfinding errors. In contrast, disrupting differentiation by expression of dominant-negative Ras GTPase in glia resulted in major sensory axon pathfinding errors, similar to those seen in glial ablations. Glial overexpression of transgenic components of the epidermal growth factor receptor (EGFR) signaling pathway yielded similar sensory neuron defects and also downregulated the expression of the glial marker Neuroglian. Mutant analysis also suggested that the EGFR ligands Spitz and Vein play roles in peripheral glial development. The observations support a model in which glia express genes necessary for sensory neuron development, and these genes are potentially under the control of the EGFR/Ras signaling pathway.

Netrins and UNC5 receptors in angiogenesis.

PubMed

Freitas, Catarina; Larrivée, Bruno; Eichmann, Anne

2008-01-01

Both neuronal and vascular development require guidance to establish a precise branching pattern of these systems in the vertebrate body. Several molecules implicated in axon navigation have also been shown to regulate vessel sprouting. Among these guidance cues, Netrins constitute a family of diffusible molecules with a bifuncional role in axon pathfinding. Recent findings implicate Netrins in other developmental processes, including vascular development. We here review recent studies and discuss the possible dual function of Netrins and its receptors during branching of blood vessels in developmental and pathological angiogenesis.

Activation of epidermal growth factor receptor mediates receptor axon sorting and extension in the developing olfactory system of the moth Manduca sexta.

PubMed

Gibson, Nicholas J; Tolbert, Leslie P

2006-04-10

During development of the adult olfactory system of the moth Manduca sexta, olfactory receptor neurons extend axons from the olfactory epithelium in the antenna into the brain. As they arrive at the brain, interactions with centrally derived glial cells cause axons to sort and fasciculate with other axons destined to innervate the same glomeruli. Here we report studies indicating that activation of the epidermal growth factor receptor (EGFR) is involved in axon ingrowth and targeting. Blocking the EGFR kinase domain pharmacologically leads to stalling of many axons in the sorting zone and nerve layer as well as abnormal axonal fasciculation in the sorting zone. We also find that neuroglian, an IgCAM known to activate the EGFR through homophilic interactions in other systems, is transiently present on olfactory receptor neuron axons and on glia during the critical stages of the sorting process. The neuroglian is resistant to extraction with Triton X-100 in the sorting zone and nerve layer, possibly indicating its stabilization by homophilic binding in these regions. Our results suggest a mechanism whereby neuroglian molecules on axons and possibly sorting zone glia bind homophilically, leading to activation of EGFRs, with subsequent effects on axon sorting, pathfinding, and extension, and glomerulus development. Copyright 2006 Wiley-Liss, Inc.

Activation of EGF Receptor Mediates Receptor Axon Sorting and Extension in the Developing Olfactory System of the Moth Manduca sexta

PubMed Central

Gibson, Nicholas J.; Tolbert, Leslie P.

2008-01-01

During development of the adult olfactory system of the moth Manduca sexta, olfactory receptor neurons extend axons from the olfactory epithelium in the antenna into the brain. As they arrive at the brain, interactions with centrally-derived glial cells cause axons to sort and fasciculate with other axons destined to innervate the same glomeruli. Here we report studies that indicate that activation of the epidermal growth factor receptor (EGFR) is involved in axon ingrowth and targeting. Blocking the EGFR kinase domain pharmacologically leads to stalling of many axons in the sorting zone and nerve layer, as well as abnormal axonal fasciculation in the sorting zone. We also find that neuroglian, an IgCAM known to activate the EGFR through homophilic interactions in other systems, is transiently present on olfactory receptor neuron axons and on glia during the critical stages of the sorting process. The neuroglian is resistant to extraction with Triton X-100 in the sorting zone and nerve layer, possibly indicating its stabilization by homophilic binding in these regions. Our results suggest a mechanism whereby neuroglian molecules on axons and possibly sorting zone glia bind homophilically, leading to activation of EGFRs with subsequent effects on axon sorting, pathfinding, and extension, and glomerulus development. PMID:16498681

The "waiting period" of sensory and motor axons in early chick hindlimb: its role in axon pathfinding and neuronal maturation.

PubMed

Wang, G; Scott, S A

2000-07-15

During embryonic development motor axons in the chick hindlimb grow out slightly before sensory axons and wait in the plexus region at the base of the limb for approximately 24 hr before invading the limb itself (Tosney and Landmesser, 1985a). We have investigated the role of this waiting period by asking, Is the arrest of growth cones in the plexus region a general property of both sensory and motor axons? Why do axons wait? Does eliminating the waiting period affect the further development of motor and sensory neurons? Here we show that sensory axons, like motor axons, pause in the plexus region and that neither sensory nor motor axons require cues from the other population to wait in or exit from the plexus region. By transplanting older or younger donor limbs to host embryos, we show that host axons innervate donor limbs on a schedule consistent with the age of the grafted limbs. Thus, axons wait in the plexus region for maturational changes to occur in the limb rather than in the neurons themselves. Both sensory and motor axons innervate their appropriate peripheral targets when the waiting period is eliminated by grafting older donor limbs. Therefore, axons do not require a prolonged period in the plexus region to sort out and project appropriately. Eliminating the waiting period does, however, accelerate the onset of naturally occurring cell death, but it does not enhance the development of central projections or the biochemical maturation of sensory neurons.

Axonal/Glial Upregulation of EphB/ephrin-B Signaling in Mouse Experimental Ocular Hypertension

PubMed Central

Tran, Tony; Sretavan, David

2010-01-01

Purpose. To use a laser-induced ocular hypertension (LIOH) mouse model to examine the optic nerve head (ONH) expression of EphB/ephrin-B, previously shown to be upregulated in glaucomatous DBA/2J mice. To relate ephrin-B reverse signaling with states of axonal response to disease. Methods. LIOH was induced unilaterally in CD-1 mice by laser photocoagulation of limbal and episcleral veins. Intraocular pressure (IOP) was measured with a tonometer. EphB/ephrin-B mRNA expression was assessed by in situ hybridization on eyecup cryosections and real-time PCR. Cell specific markers were used to identify the cellular origin of EphB/ephrin-B expression. Activation of ephrin-B signaling was investigated with a phosphospecific antibody on cryosections and retinal whole-mounts. Results. Upregulation of EphB/ephrin-B expression occurred early within a day of IOP elevation. A transient increase of phosphorylation-dependent ephrin-B (pEB) reverse signaling was observed in ONH axons, microglia, and some astrocytes. Morphologically unaffected retinal ganglion cell (RGC) axons differed from axons with reactive aberrant trajectories by exhibiting increased pEB activation, whereas pEB levels in morphologically affected axons were comparable to those of controls. Conclusions. An Eph-ephrin signaling network is activated at the ONH after LIOH in CD-1 mice, either before or coincident with the initial morphologic signs of RGC axon damage reported previously. Of note, ephrin-B reverse signaling was transiently upregulated in RGC axons at the ONH early in their response to IOP elevation but was downregulated in axons that had been damaged by glaucomatous injury and exhibited aberrant trajectories. Ephrin-B reverse signaling may mark RGC axons for damage or confer a protective advantage against injury. PMID:19815726

Rab5 and Rab4 Regulate Axon Elongation in the Xenopus Visual System

PubMed Central

Konopacki, Filip A.; Zivraj, Krishna H.; Holt, Christine E.

2014-01-01

The elongation rate of axons is tightly regulated during development. Recycling of the plasma membrane is known to regulate axon extension; however, the specific molecules involved in recycling within the growth cone have not been fully characterized. Here, we investigated whether the small GTPases Rab4 and Rab5 involved in short-loop recycling regulate the extension of Xenopus retinal axons. We report that, in growth cones, Rab5 and Rab4 proteins localize to endosomes, which accumulate markers that are constitutively recycled. Fluorescence recovery after photo-bleaching experiments showed that Rab5 and Rab4 are recruited to endosomes in the growth cone, suggesting that they control recycling locally. Dynamic image analysis revealed that Rab4-positive carriers can bud off from Rab5 endosomes and move to the periphery of the growth cone, suggesting that both Rab5 and Rab4 contribute to recycling within the growth cone. Inhibition of Rab4 function with dominant-negative Rab4 or Rab4 morpholino and constitutive activation of Rab5 decreases the elongation of retinal axons in vitro and in vivo, but, unexpectedly, does not disrupt axon pathfinding. Thus, Rab5- and Rab4-mediated control of endosome trafficking appears to be crucial for axon growth. Collectively, our results suggest that recycling from Rab5-positive endosomes via Rab4 occurs within the growth cone and thereby supports axon elongation. PMID:24403139

Use of double-stranded RNA-mediated interference to determine the substrates of protein tyrosine kinases and phosphatases.

PubMed

Muda, Marco; Worby, Carolyn A; Simonson-Leff, Nancy; Clemens, James C; Dixon, Jack E

2002-08-15

Despite the wealth of information generated by genome-sequencing projects, the identification of in vivo substrates of specific protein kinases and phosphatases is hampered by the large number of candidate enzymes, overlapping enzyme specificity and sequence similarity. In the present study, we demonstrate the power of RNA interference (RNAi) to dissect signal transduction cascades involving specific kinases and phosphatases. RNAi is used to identify the cellular tyrosine kinases upstream of the phosphorylation of Down-Syndrome cell-adhesion molecule (Dscam), a novel cell-surface molecule of the immunoglobulin-fibronectin super family, which has been shown to be important for axonal path-finding in Drosophila. Tyrosine phosphorylation of Dscam recruits the Src homology 2 domain of the adaptor protein Dock to the receptor. Dock, the ortho- logue of mammalian Nck, is also essential for correct axonal path-finding in Drosophila. We further determined that Dock is tyrosine-phosphorylated in vivo and identified DPTP61F as the protein tyrosine phosphatase responsible for maintaining Dock in its non-phosphorylated state. The present study illustrates the versatility of RNAi in the identification of the physiological substrates for protein kinases and phosphatases.

Activation of EGF receptor kinase by L1-mediated homophilic cell interactions.

PubMed

Islam, Rafique; Kristiansen, Lars V; Romani, Susana; Garcia-Alonso, Luis; Hortsch, Michael

2004-04-01

Neural cell adhesion molecules (CAMs) are important players during neurogenesis and neurite outgrowth as well as axonal fasciculation and pathfinding. Some of these developmental processes entail the activation of cellular signaling cascades. Pharmacological and genetic evidence indicates that the neurite outgrowth-promoting activity of L1-type CAMs is at least in part mediated by the stimulation of neuronal receptor tyrosine kinases (RTKs), especially FGF and EGF receptors. It has long been suspected that neural CAMs might physically interact with RTKs, but their activation by specific cell adhesion events has not been directly demonstrated. Here we report that gain-of-function conditions of the Drosophila L1-type CAM Neuroglian result in profound sensory axon pathfinding defects in the developing Drosophila wing. This phenotype can be suppressed by decreasing the normal gene dosage of the Drosophila EGF receptor gene. Furthermore, in Drosophila S2 cells, cell adhesion mediated by human L1-CAM results in the specific activation of human EGF tyrosine kinase at cell contact sites and EGF receptors engage in a physical interaction with L1-CAM molecules. Thus L1-type CAMs are able to promote the adhesion-dependent activation of EGF receptor signaling in vitro and in vivo.

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

PubMed Central

Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie-Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann-Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F. A.; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; McPherson, John D.; Gibbs, Richard A.; Grimmond, Sean M.

2012-01-01

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PMID:23103869

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

PubMed

Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

2012-11-15

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Transcriptional regulation of neuronal polarity and morphogenesis in the mammalian brain

PubMed Central

de la Torre-Ubieta, Luis; Bonni, Azad

2012-01-01

The highly specialized morphology of a neuron, typically consisting of a long axon and multiple branching dendrites, lies at the core of the principle of dynamic polarization, whereby information flows from dendrites toward the soma and to the axon. For more than a century neuroscientists have been fascinated by how shape is important for neuronal function and how neurons acquire their characteristic morphology. During the past decade, substantial progress has been made in our understanding of the molecular underpinnings of neuronal polarity and morphogenesis. In these studies, transcription factors have emerged as key players governing multiple aspects of neuronal morphogenesis from neuronal polarization and migration to axon growth and pathfinding to dendrite growth and branching to synaptogenesis. In this review, we will highlight the role of transcription factors in shaping neuronal morphology with emphasis on recent literature in mammalian systems. PMID:21982366

Growth cone travel in space and time: the cellular ensemble of cytoskeleton, adhesion, and membrane.

PubMed

Vitriol, Eric A; Zheng, James Q

2012-03-22

Growth cones, found at the tip of axonal projections, are the sensory and motile organelles of developing neurons that enable axon pathfinding and target recognition for precise wiring of the neural circuitry. To date, many families of conserved guidance molecules and their corresponding receptors have been identified that work in space and time to ensure billions of axons to reach their targets. Research in the past two decades has also gained significant insight into the ways in which growth cones translate extracellular signals into directional migration. This review aims to examine new progress toward understanding the cellular mechanisms underlying directional motility of the growth cone and to discuss questions that remain to be addressed. Specifically, we will focus on the cellular ensemble of cytoskeleton, adhesion, and membrane and examine how the intricate interplay between these processes orchestrates the directed movement of growth cones. Copyright © 2012 Elsevier Inc. All rights reserved.

Concentration dependent requirement for local protein synthesis in motor neuron subtype specific response to axon guidance cues

PubMed Central

Nedelec, Stephane; Peljto, Mirza; Shi, Peng; Amoroso, Mackenzie W.; Kam, Lance C.; Wichterle, Hynek

2012-01-01

Formation of functional motor circuits relies on the ability of distinct spinal motor neuron subtypes to project their axons with high precision to appropriate muscle targets. While guidance cues contributing to motor axon pathfinding have been identified, the intracellular pathways underlying subtype specific responses to these cues remain poorly understood. In particular, it remains controversial whether responses to axon guidance cues depend on axonal protein synthesis. Using a growth cone collapse assay, we demonstrate that mouse embryonic stem cell (ESC) derived spinal motor neurons (ES-MNs) respond to ephrin-A5, Sema3f and Sema3a in a concentration dependent manner. At low doses, ES-MNs exhibit segmental or subtype specific responses, while this selectivity is lost at higher concentrations. Response to high doses of semaphorins and to all doses of ephrin-A5 is protein synthesis independent. In contrast, using microfluidic devices and stripe assays, we show that growth cone collapse and guidance at low concentrations of semaphorins relies on local protein synthesis in the axonal compartment. Similar bimodal response to low and high concentrations of guidance cues is observed in human ES-MNs, pointing to a general mechanism by which neurons increase their repertoire of responses to the limited set of guidance cues involved in neural circuit formation. PMID:22279234

LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes.

PubMed

Fu, Meng-Meng; Nirschl, Jeffrey J; Holzbaur, Erika L F

2014-06-09

Autophagy is essential for maintaining cellular homeostasis in neurons, where autophagosomes undergo robust unidirectional retrograde transport along axons. We find that the motor scaffolding protein JIP1 binds directly to the autophagosome adaptor LC3 via a conserved LIR motif. This interaction is required for the initial exit of autophagosomes from the distal axon, for sustained retrograde transport along the midaxon, and for autophagosomal maturation in the proximal axon. JIP1 binds directly to the dynein activator dynactin but also binds to and activates kinesin-1 in a phosphorylation-dependent manner. Following JIP1 depletion, phosphodeficient JIP1-S421A rescues retrograde transport, while phosphomimetic JIP1-S421D aberrantly activates anterograde transport. During normal autophagosome transport, residue S421 of JIP1 may be maintained in a dephosphorylated state by autophagosome-associated MKP1 phosphatase. Moreover, binding of LC3 to JIP1 competitively disrupts JIP1-mediated activation of kinesin. Thus, dual mechanisms prevent aberrant activation of kinesin to ensure robust retrograde transport of autophagosomes along the axon. Copyright © 2014 Elsevier Inc. All rights reserved.

Aberrant Axonal Arborization of PDF Neurons Induced by Aβ42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.

PubMed

Song, Qian; Feng, Ge; Huang, Zehua; Chen, Xiaoman; Chen, Zhaohuan; Ping, Yong

2017-10-01

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.

Npn-1 Contributes to Axon-Axon Interactions That Differentially Control Sensory and Motor Innervation of the Limb

PubMed Central

Bianchi, Elisa; Novitch, Bennett G.; Huber, Andrea B.

2011-01-01

The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs. PMID:21364975

Foxg1 regulates retinal axon pathfinding by repressing an ipsilateral program in nasal retina and by causing optic chiasm cells to exert a net axonal growth-promoting activity.

PubMed

Tian, Natasha M; Pratt, Thomas; Price, David J

2008-12-01

Mammalian binocular vision relies on the divergence of retinal ganglion cell axons at the optic chiasm, with strictly controlled numbers projecting contralaterally and ipsilaterally. In mouse, contralateral projections arise from the entire retina, whereas ipsilateral projections arise from ventrotemporal retina. We investigate how development of these patterns of projection is regulated by the contralateral determinant Foxg1, a forkhead box transcription factor expressed in nasal retina and at the chiasm. In nasal retina, loss of Foxg1 causes increased numbers of ipsilateral projections and ectopic expression of the ipsilateral determinants Zic2, Ephb1 and Foxd1, indicating that nasal retina is competent to express an ipsilateral program that is normally suppressed by Foxg1. Using co-cultures that combine Foxg1-expressing with Foxg1-null retinal explants and chiasm cells, we provide functional evidence that Foxg1 promotes contralateral projections through actions in nasal retina, and that in chiasm cells, Foxg1 is required for the generation of a hitherto unrecognized activity supporting RGC axon growth.

Mechanosensilla in the adult abdomen of Drosophila: engrailed and slit help to corral the peripheral sensory axons into segmental bundles.

PubMed

Fabre, Caroline C G; Casal, José; Lawrence, Peter A

2010-09-01

The abdomen of adult Drosophila bears mechanosensory bristles with axons that connect directly to the CNS, each hemisegment contributing a separate nerve bundle. Here, we alter the amount of Engrailed protein and manipulate the Hedgehog signalling pathway in clones of cells to study their effects on nerve pathfinding within the peripheral nervous system. We find that high levels of Engrailed make the epidermal cells inhospitable to bristle neurons; sensory axons that are too near these cells are either deflected or fail to extend properly or at all. We then searched for the engrailed-dependent agent responsible for these repellent properties. We found slit to be expressed in the P compartment and, using genetic mosaics, present evidence that Slit is the responsible molecule. Blocking the activity of the three Robo genes (putative receptors for Slit) with RNAi supported this hypothesis. We conclude that, during normal development, gradients of Slit protein repel axons away from compartment boundaries - in consequence, the bristles from each segment send their nerves to the CNS in separated sets.

Activation of EGF Receptor Kinase by L1-mediated Homophilic Cell Interactions

PubMed Central

Islam, Rafique; Kristiansen, Lars V.; Romani, Susana; Garcia-Alonso, Luis; Hortsch, Michael

2004-01-01

Neural cell adhesion molecules (CAMs) are important players during neurogenesis and neurite outgrowth as well as axonal fasciculation and pathfinding. Some of these developmental processes entail the activation of cellular signaling cascades. Pharmacological and genetic evidence indicates that the neurite outgrowth-promoting activity of L1-type CAMs is at least in part mediated by the stimulation of neuronal receptor tyrosine kinases (RTKs), especially FGF and EGF receptors. It has long been suspected that neural CAMs might physically interact with RTKs, but their activation by specific cell adhesion events has not been directly demonstrated. Here we report that gain-of-function conditions of the Drosophila L1-type CAM Neuroglian result in profound sensory axon pathfinding defects in the developing Drosophila wing. This phenotype can be suppressed by decreasing the normal gene dosage of the Drosophila EGF receptor gene. Furthermore, in Drosophila S2 cells, cell adhesion mediated by human L1-CAM results in the specific activation of human EGF tyrosine kinase at cell contact sites and EGF receptors engage in a physical interaction with L1-CAM molecules. Thus L1-type CAMs are able to promote the adhesion-dependent activation of EGF receptor signaling in vitro and in vivo. PMID:14718570

Guidance of retinal axons in mammals.

PubMed

Herrera, Eloísa; Erskine, Lynda; Morenilla-Palao, Cruz

2017-11-26

In order to navigate through the surrounding environment many mammals, including humans, primarily rely on vision. The eye, composed of the choroid, sclera, retinal pigmented epithelium, cornea, lens, iris and retina, is the structure that receives the light and converts it into electrical impulses. The retina contains six major types of neurons involving in receiving and modifying visual information and passing it onto higher visual processing centres in the brain. Visual information is relayed to the brain via the axons of retinal ganglion cells (RGCs), a projection known as the optic pathway. The proper formation of this pathway during development is essential for normal vision in the adult individual. Along this pathway there are several points where visual axons face 'choices' in their direction of growth. Understanding how these choices are made has advanced significantly our knowledge of axon guidance mechanisms. Thus, the development of the visual pathway has served as an extremely useful model to reveal general principles of axon pathfinding throughout the nervous system. However, due to its particularities, some cellular and molecular mechanisms are specific for the visual circuit. Here we review both general and specific mechanisms involved in the guidance of mammalian RGC axons when they are traveling from the retina to the brain to establish precise and stereotyped connections that will sustain vision. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spatial temperature gradients guide axonal outgrowth

PubMed Central

Black, Bryan; Vishwakarma, Vivek; Dhakal, Kamal; Bhattarai, Samik; Pradhan, Prabhakar; Jain, Ankur; Kim, Young-tae; Mohanty, Samarendra

2016-01-01

Formation of neural networks during development and regeneration after injury depends on accuracy of axonal pathfinding, which is primarily believed to be influenced by chemical cues. Recently, there is growing evidence that physical cues can play crucial role in axonal guidance. However, detailed mechanism involved in such guidance cues is lacking. By using weakly-focused near-infrared continuous wave (CW) laser microbeam in the path of an advancing axon, we discovered that the beam acts as a repulsive guidance cue. Here, we report that this highly-effective at-a-distance guidance is the result of a temperature field produced by the near-infrared laser light absorption. Since light absorption by extracellular medium increases when the laser wavelength was red shifted, the threshold laser power for reliable guidance was significantly lower in the near-infrared as compared to the visible spectrum. The spatial temperature gradient caused by the near-infrared laser beam at-a-distance was found to activate temperature-sensitive membrane receptors, resulting in an influx of calcium. The repulsive guidance effect was significantly reduced when extracellular calcium was depleted or in the presence of TRPV1-antagonist. Further, direct heating using micro-heater confirmed that the axonal guidance is caused by shallow temperature-gradient, eliminating the role of any non-photothermal effects. PMID:27460512

Spatial temperature gradients guide axonal outgrowth

NASA Astrophysics Data System (ADS)

Black, Bryan; Vishwakarma, Vivek; Dhakal, Kamal; Bhattarai, Samik; Pradhan, Prabhakar; Jain, Ankur; Kim, Young-Tae; Mohanty, Samarendra

2016-07-01

Formation of neural networks during development and regeneration after injury depends on accuracy of axonal pathfinding, which is primarily believed to be influenced by chemical cues. Recently, there is growing evidence that physical cues can play crucial role in axonal guidance. However, detailed mechanism involved in such guidance cues is lacking. By using weakly-focused near-infrared continuous wave (CW) laser microbeam in the path of an advancing axon, we discovered that the beam acts as a repulsive guidance cue. Here, we report that this highly-effective at-a-distance guidance is the result of a temperature field produced by the near-infrared laser light absorption. Since light absorption by extracellular medium increases when the laser wavelength was red shifted, the threshold laser power for reliable guidance was significantly lower in the near-infrared as compared to the visible spectrum. The spatial temperature gradient caused by the near-infrared laser beam at-a-distance was found to activate temperature-sensitive membrane receptors, resulting in an influx of calcium. The repulsive guidance effect was significantly reduced when extracellular calcium was depleted or in the presence of TRPV1-antagonist. Further, direct heating using micro-heater confirmed that the axonal guidance is caused by shallow temperature-gradient, eliminating the role of any non-photothermal effects.

After facial nerve damage, regenerating axons become aberrant throughout the length of the nerve and not only at the site of the lesion: an experimental study.

PubMed

Choi, D; Raisman, G

2004-02-01

After facial nerve trauma, aberrant regeneration is associated with synkinesis. Animal models of mechanical nerve guides or reparative cell transplants at the site of a lesion have not been shown to improve disorganized regeneration. We examined whether this is because regenerating axons become disorganized throughout the length of the nerve and not only at the site of the lesion. In rats (n = 12), retrograde fluorescent tracer techniques were used to establish that most of the temporal branch fibres were carried in the superior half of the facial nerve trunk. In two further groups of rats (n = 24) a complete proximal facial nerve lesion was made, and the nerve immediately repaired by suture. After 4 weeks, at a second operation, the superior half of the facial nerve trunk was cut, either proximal or distal to the original lesion, and retrograde tracers were applied to distal branches of the nerve. It was possible to localize the points at which regenerating fibres became aberrant in their course by studying the number of labelled motoneurons in the facial nucleus after application of the tracer to the temporal branch of the nerve: this was similar in the distal and proximal hemisection groups, suggesting that aberrant axonal development occurred throughout the length of the nerve. Future strategies aimed at improving the organization of regeneration need to provide guidance cues not only at the site of the lesion as previously thought, but also throughout the length of the nerve.

Regulation of axonal development by the nuclear protein hindsight (pebbled) in the Drosophila visual system.

PubMed

Oliva, Carlos; Sierralta, Jimena

2010-08-15

The molecules and networks involved in the process of acquisition and maintenance of the form of a mature neuron are not completely known. Using a misexpression screen we identified the gene hindsight as a gene involved in the process of acquisition of the neuronal morphogenesis in the Drosophila adult nervous system. hindsight encodes a transcription factor known for its role in early developmental processes such as embryonic germ band retraction and dorsal closure, as well as in the establishment of cell morphology, planar cell polarity, and epithelial integrity during retinal development. We describe here a novel function for HNT by showing that both loss and gain of function of HNT affects the pathfinding of the photoreceptors axons. By manipulating the timing and level of HNT expression, together with the number of cells manipulated we show here that the function of HNT in axonal guidance is independent of the HNT functions previously reported in retinal cells. Based on genetic interaction experiments we show that part of HNT function in axonal development is exerted through the regulation of genes involved in the dynamics of the actin cytoskeleton. Copyright 2010 Elsevier Inc. All rights reserved.

Virtual tissue engineering and optic pathways: plotting the course of the axons in the retinal nerve fiber layer.

PubMed

Carreras, Francisco Javier; Medina, Javier; Ruiz-Lozano, Mariola; Carreras, Ignacio; Castro, Juan Luis

2014-04-17

As part of a larger project on virtual tissue engineering of the optic pathways, we describe the conditions that guide axons extending from the retina to the optic nerve head and formulate algorithms that meet such conditions. To find the entrance site on the optic nerve head of each axon, we challenge the fibers to comply with current models of axonal pathfinding. First, we build a retinal map using a single type of retinal ganglion cell (RGC) using density functions from the literature. Dendritic arbors are equated to receptive fields. Shape and size of retinal surface and optic nerve head (ONH) are defined. A computer model relates each soma to the corresponding entry point of its axon into the optic disc. Weights are given to the heuristics that guide the preference entry order in the nerve. Retinal ganglion cells from the area centralis saturate the temporal section of the disc. Retinal ganglion cells temporal to the area centralis curve their paths surrounding the fovea; some of these cells enter the disc centrally rather than peripherally. Nasal regions of the disc receive mixed axons from the far periphery of the temporal hemiretina, together with axons from the nasal half. The model plots the course of the axon using Bezier curves and compares them with clinical data, for a coincidence level of 86% or higher. Our model is able to simulate basic data of the early optic pathways including certain singularities and to mimic mechanisms operating during development, such as timing and fasciculation. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Characterization of axon formation in the embryonic stem cell-derived motoneuron.

PubMed

Pan, Hung-Chuan; Wu, Ya-Ting; Shen, Shih-Cheng; Wang, Chi-Chung; Tsai, Ming-Shiun; Cheng, Fu-Chou; Lin, Shinn-Zong; Chen, Ching-Wen; Liu, Ching-San; Su, Hong-Lin

2011-01-01

The developing neural cell must form a highly organized architecture to properly receive and transmit nerve signals. Neural formation from embryonic stem (ES) cells provides a novel system for studying axonogenesis, which are orchestrated by polarity-regulating molecules. Here the ES-derived motoneurons, identified by HB9 promoter-driven green fluorescent protein (GFP) expression, showed characteristics of motoneuron-specific gene expression. In the majority of motoneurons, one of the bilateral neurites developed into an axon that featured with axonal markers, including Tau1, vesicle acetylcholine transporter, and synaptophysin. Interestingly, one third of the motoneurons developed bi-axonal processes but no multiple axonal GFP cell was found. The neuronal polarity-regulating proteins, including the phosphorylated AKT and ERK, were compartmentalized into both of the bilateral axonal tips. Importantly, this aberrant axon morphology was still present after the engraftment of GFP(+) neurons into the spinal cord, suggesting that even a mature neural environment fails to provide a proper niche to guide normal axon formation. These findings underscore the necessity for evaluating the morphogenesis and functionality of neurons before the clinical trials using ES or somatic stem cells.

Use of polysialic acid in repair of the central nervous system

PubMed Central

El Maarouf, Abderrahman; Petridis, Athanasios K.; Rutishauser, Urs

2006-01-01

Polysialic acid (PSA), a large cell-surface carbohydrate that regulates cell interactions, is used during vertebrate development to promote precursor cell migration and axon path-finding. The induction of PSA expression in damaged adult CNS tissues could help them to rebuild by creating conditions permissive for architectural remodeling. This possibility has been explored in two contexts, the regeneration of axons and the recruitment of endogenous neural precursors to a lesion. Glial scars that form at CNS injury sites block axon regeneration. It has been found that transfection of scar astrocytes by a viral vector encoding polysialyltransferase leads to sustained expression of high levels of PSA. With this treatment, a substantial portion of severed corticospinal tract axon processes were able to grow through a spinal injury site. In the studies of precursor cell migration to a cortical lesion, it was found that induced PSA expression in a path extending from the subventricular zone to a lesion near the cortical surface increased recruitment of BrdU/nestin-positive cells along the path and into the injury site. These displaced precursors were able to differentiate in a regionally appropriate manner. These findings suggest that induced PSA expression can be used as a strategy for promoting tissue repair involving both replacement of cells and rebuilding of neural connections. PMID:17075041

Jab1 regulates Schwann cell proliferation and axonal sorting through p27

PubMed Central

Porrello, Emanuela; Rivellini, Cristina; Dina, Giorgia; Triolo, Daniela; Del Carro, Ubaldo; Ungaro, Daniela; Panattoni, Martina; Feltri, Maria Laura; Wrabetz, Lawrence; Pardi, Ruggero; Quattrini, Angelo

2014-01-01

Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211– and, possibly, neuregulin 1 (Nrg1)–derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain–binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies. PMID:24344238

Microtubule behavior in the growth cones of living neurons during axon elongation

PubMed Central

1991-01-01

To understand how microtubules are generated in the growth cone, we have imaged fluorescently tagged microtubules in living frog embryonic neurons. The neurons were labeled by injecting rhodamine-labeled tubulin into the fertilized egg and explanting the neurons from the neural tube. Microtubules extend deep into the growth cone periphery and adopt three characteristic distributions: (a) dispersed and splayed throughout much of the growth cone; (b) looped and apparently contorted by compression; and (c) bundled into tight arrays. These distributions interconvert on a time scale of several minutes and these interconversions are correlated with the behavior of the growth cone. We observed microtubule growth and shrinkage in growth cones, but are unable to determine their contribution to net assembly. However, translocation of polymer form the axon appears to be a major mechanism of generating new polymer in the growth cone, while bundling of microtubules in the growth cone appears to be the critical step in generating new axon. Neurons that were about to turn spontaneously generated microtubules in the future direction of growth, suggesting that orientation of microtubules might be an important early step in neuronal pathfinding. PMID:1918145

Use of a Y-tube conduit after facial nerve injury reduces collateral axonal branching at the lesion site but neither reduces polyinnervation of motor endplates nor improves functional recovery.

PubMed

Hizay, Arzu; Ozsoy, Umut; Demirel, Bahadir Murat; Ozsoy, Ozlem; Angelova, Srebrina K; Ankerne, Janina; Sarikcioglu, Sureyya Bilmen; Dunlop, Sarah A; Angelov, Doychin N; Sarikcioglu, Levent

2012-06-01

Despite increased understanding of peripheral nerve regeneration, functional recovery after surgical repair remains disappointing. A major contributing factor is the extensive collateral branching at the lesion site, which leads to inaccurate axonal navigation and aberrant reinnervation of targets. To determine whether the Y tube reconstruction improved axonal regrowth and whether this was associated with improved function. We used a Y-tube conduit with the aim of improving navigation of regenerating axons after facial nerve transection in rats. Retrograde labeling from the zygomatic and buccal branches showed a halving in the number of double-labeled facial motor neurons (15% vs 8%; P < .05) after Y tube reconstruction compared with facial-facial anastomosis coaptation. However, in both surgical groups, the proportion of polyinnervated motor endplates was similar (≈ 30%; P > .05), and video-based motion analysis of whisking revealed similarly poor function. Although Y-tube reconstruction decreases axonal branching at the lesion site and improves axonal navigation compared with facial-facial anastomosis coaptation, it fails to promote monoinnervation of motor endplates and confers no functional benefit.

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

PubMed Central

Naftelberg, Shiran; Abramovitch, Ziv; Gluska, Shani; Yannai, Sivan; Joshi, Yuvraj; Donyo, Maya; Ben-Yaakov, Keren; Gradus, Tal; Zonszain, Jonathan; Farhy, Chen; Ashery-Padan, Ruth

2016-01-01

Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of α-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of α-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration. PMID:27997532

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia.

PubMed

Naftelberg, Shiran; Abramovitch, Ziv; Gluska, Shani; Yannai, Sivan; Joshi, Yuvraj; Donyo, Maya; Ben-Yaakov, Keren; Gradus, Tal; Zonszain, Jonathan; Farhy, Chen; Ashery-Padan, Ruth; Perlson, Eran; Ast, Gil

2016-12-01

Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of α-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of α-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration.

Microtubule-Actin Crosslinking Factor 1 Is Required for Dendritic Arborization and Axon Outgrowth in the Developing Brain.

PubMed

Ka, Minhan; Kim, Woo-Yang

2016-11-01

Dendritic arborization and axon outgrowth are critical steps in the establishment of neural connectivity in the developing brain. Changes in the connectivity underlie cognitive dysfunction in neurodevelopmental disorders. However, molecules and associated mechanisms that play important roles in dendritic and axon outgrowth in the brain are only partially understood. Here, we show that microtubule-actin crosslinking factor 1 (MACF1) regulates dendritic arborization and axon outgrowth of developing pyramidal neurons by arranging cytoskeleton components and mediating GSK-3 signaling. MACF1 deletion using conditional mutant mice and in utero gene transfer in the developing brain markedly decreased dendritic branching of cortical and hippocampal pyramidal neurons. MACF1-deficient neurons showed reduced density and aberrant morphology of dendritic spines. Also, loss of MACF1 impaired the elongation of callosal axons in the brain. Actin and microtubule arrangement appeared abnormal in MACF1-deficient neurites. Finally, we found that GSK-3 is associated with MACF1-controlled dendritic differentiation. Our findings demonstrate a novel role for MACF1 in neurite differentiation that is critical to the creation of neuronal connectivity in the developing brain.

A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation.

PubMed

Godenschwege, Tanja A; Kristiansen, Lars V; Uthaman, Smitha B; Hortsch, Michael; Murphey, Rodney K

2006-01-10

Drosophila Neuroglian (Nrg) and its vertebrate homolog L1-CAM are cell-adhesion molecules (CAM) that have been well studied in early developmental processes. Mutations in the human gene result in a broad spectrum of phenotypes (the CRASH-syndrome) that include devastating neurological disorders such as spasticity and mental retardation. Although the role of L1-CAMs in neurite extension and axon pathfinding has been extensively studied, much less is known about their role in synapse formation. We found that a single extracellular missense mutation in nrg(849) mutants disrupted the physiological function of a central synapse in Drosophila. The identified giant neuron in nrg(849) mutants made a synaptic terminal on the appropriate target, but ultrastructural analysis revealed in the synaptic terminal a dramatic microtubule reduction, which was likely to be the cause for disrupted active zones. Our results reveal that tyrosine phosphorylation of the intracellular ankyrin binding motif was reduced in mutants, and cell-autonomous rescue experiments demonstrated the indispensability of this tyrosine in giant-synapse formation. We also show that this function in giant-synapse formation was conserved in human L1-CAM but neither in human L1-CAM with a pathological missense mutation nor in two isoforms of the paralogs NrCAM and Neurofascin. We conclude that Nrg has a function in synapse formation by organizing microtubules in the synaptic terminal. This novel synaptic function is conserved in human L1-CAM but is not common to all L1-type proteins. Finally, our findings suggest that some aspects of L1-CAM-related neurological disorders in humans may result from a disruption in synapse formation rather than in axon pathfinding.

Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging.

PubMed

Su, Weiping; Xing, Rubing; Guha, Abhijit; Gutmann, David H; Sherman, Larry S

2007-05-01

Neurofibromatosis 1 (NF1) is a common genetic disease that predisposes patients to peripheral nerve tumors and central nervous system (CNS) abnormalities including low-grade astrocytomas and cognitive disabilities. Using mice with glial fibrillary acidic protein (GFAP)-targeted Nf1 loss (Nf1(GFAP)CKO mice), we found that Nf1(-/-) astrocytes proliferate faster and are more invasive than wild-type astrocytes. In light of our previous finding that aberrant expression of the MET receptor tyrosine kinase contributes to the invasiveness of human NF1-associated malignant peripheral nerve sheath tumors, we sought to determine whether MET expression is aberrant in the brains of Nf1 mutant mice. We found that Nf1(-/-) astrocytes express slightly more MET than wild-type cells in vitro, but do not express elevated MET in situ. However, fiber tracts containing myelinated axons in the hippocampus, midbrain, cerebral cortex, and cerebellum express higher than normal levels of MET in older (> or =6 months) Nf1(GFAP)CKO mice. Both Nf1(GFAP)CKO and wild-type astrocytes induced MET expression in neurites of wild-type hippocampal neurons in vitro, suggesting that astrocyte-derived signals may induce MET in Nf1 mutant mice. Because the Nf1 gene product functions as a RAS GTPase, we examined MET expression in the brains of mice with GFAP-targeted constitutively active forms of RAS. MET was elevated in axonal fiber tracts in mice with active K-RAS but not H-RAS. Collectively, these data suggest that loss of Nf1 in either astrocytes or GFAP(+) neural progenitor cells results in increased axonal MET expression, which may contribute to the CNS abnormalities in children and adults with NF1. (c) 2007 Wiley-Liss, Inc.

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve.

PubMed

Sarabia-Estrada, Rachel; Bañuelos-Pineda, Jacinto; Osuna Carrasco, Laura P; Jiménez-Vallejo, Salvador; Jiménez-Estrada, Ismael; Rivas-Celis, Efrain; Dueñas-Jiménez, Judith M; Dueñas-Jiménez, Sergio H

2015-07-01

Transection of peripheral nerves produces loss of sensory and/or motor function. After complete nerve cutting, the distal and proximal segment ends retract, but if both ends are bridged with unaltered chitosan, progesterone-impregnated chitosan, or silicone tubes, an axonal repair process begins. Progesterone promotes nerve repair and has neuroprotective effects thwarting regulation of neuron survival, inflammation, and edema. It also modulates aberrant axonal sprouting and demyelination. The authors compared the efficacy of nerve recovery after implantation of progesterone-loaded chitosan, unaltered chitosan, or silicone tubes after sciatic nerve transection in rats. After surgical removal of a 5-mm segment of the proximal sciatic nerve, rats were implanted with progesterone-loaded chitosan, unaltered chitosan, or silicone tubes in the transected nerve for evaluating progesterone and chitosan effects on sciatic nerve repair and ipsilateral hindlimb kinematic function, as well as on gastrocnemius electro-myographic responses. In some experiments, tube implantation was performed 90 minutes after nerve transection. At 90 days after sciatic nerve transection and tube implantation, rats with progesterone-loaded chitosan tubes showed knee angular displacement recovery and better outcomes for step length, velocity of locomotion, and normal hindlimb raising above the ground. In contrast, rats with chitosan-only tubes showed reduced normal raising and pendulum-like hindlimb movements. Aberrant fibers coming from the tibial nerve innervated the gastrocnemius muscle, producing electromyographic responses. Electrical responses in the gastrocnemius muscle produced by sciatic nerve stimulation occurred only when the distal nerve segment was stimulated; they were absent when the proximal or intratubular segment was stimulated. A clear sciatic nerve morphology with some myelinated fiber fascicles appeared in the tube section in rats with progesterone-impregnated chitosan tubes. Some gastrocnemius efferent fibers were partially repaired 90 days after nerve resection. The better outcome in knee angle displacement may be partially attributable to the aberrant neuromuscular synaptic effects, since nerve conduction in the gastrocnemius muscle could be blocked in the progesterone-impregnated chitosan tubes. In addition, in the region of the gap produced by the nerve resection, the number of axons and amount of myelination were reduced in the sciatic nerve implanted with chitosan, progesterone-loaded chitosan, and silicone tubes. At 180 days after sciatic nerve sectioning, the knee kinematic function recovered to a level observed in control rats of a similar age. In rats with progesterone-loaded chitosan tubes, stimulation of the proximal and intratubular sciatic nerve segments produced an electromyographic response. The axon morphology of the proximal and intratubular segments of the sciatic nerve resembled that of the contralateral nontransected nerve. Progesterone-impregnated chitosan tubes produced aberrant innervation of the gastrocnemius muscle, which allowed partial recovery of gait locomotion and could be adequate for reinnervating synergistic denervated muscles while a parent innervation is reestablished. Hindlimb kinematic parameters differed between younger (those at 90 days) and older (those at 180 days) rats.

The Microtubule Regulatory Protein Stathmin Is Required to Maintain the Integrity of Axonal Microtubules in Drosophila

PubMed Central

Duncan, Jason E.; Lytle, Nikki K.; Zuniga, Alfredo; Goldstein, Lawrence S. B.

2013-01-01

Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai) gene in the maintenance of axonal microtubules and regulation of axonal transport in Drosophila . The stai gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of stai function in Drosophila , which has a single stai gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the stai gene family. This has allowed us to identify an essential function for stai in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of stai mutant Drosophila , we also observe additional neurological phenotypes associated with loss of stai function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in stai deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of Drosophila mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that stai has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport. PMID:23840848

Microtubule-Actin Crosslinking Factor 1 is required for dendritic arborization and axon outgrowth in the developing brain

PubMed Central

Ka, Minhan; Kim, Woo-Yang

2015-01-01

Dendritic arborization and axon outgrowth are critical steps in the establishment of neural connectivity in the developing brain. Changes in the connectivity underlie cognitive dysfunction in neurodevelopmental disorders. However, molecules and associated mechanisms that play important roles in dendritic and axon outgrowth in the brain are only partially understood. Here, we show that Microtubule-Actin Crosslinking Factor 1 (MACF1) regulates dendritic arborization and axon outgrowth of developing pyramidal neurons by arranging cytoskeleton components and mediating GSK-3 signaling. MACF1 deletion using conditional mutant mice and in utero gene transfer in the developing brain markedly decreased dendritic branching of cortical and hippocampal pyramidal neurons. MACF1-deficient neurons showed reduced density and aberrant morphology of dendritic spines. Also, loss of MACF1 impaired the elongation of callosal axons in the brain. Actin and microtubule arrangement appeared abnormal in MACF1-deficient neurites. Finally, we found that GSK-3 is associated with MACF1-controlled dendritic differentiation. Our findings demonstrate a novel role for MACF1 in neurite differentiation that is critical to the creation of neuronal connectivity in the developing brain. PMID:26526844

Axonal degeneration in Alzheimer’s disease: When signaling abnormalities meet the axonal transport system

PubMed Central

Kanaan, Nicholas M.; Pigino, Gustavo F.; Brady, Scott T.; Lazarov, Orly; Binder, Lester I.; Morfini, Gerardo A.

2012-01-01

Alzheimer’s disease (AD) is characterized by progressive, age-dependent degeneration of neurons in the central nervous system. A large body of evidence indicates that neurons affected in AD follow a dying-back pattern of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death. Mechanisms underlying dying-back degeneration of neurons in AD remain elusive but several have been proposed, including deficits in fast axonal transport (FAT). Accordingly, genetic evidence linked alterations in FAT to dying-back degeneration of neurons, and FAT defects have been widely documented in various AD models. In light of these findings, we discuss experimental evidence linking several AD-related pathogenic polypeptides to aberrant activation of signaling pathways involved in the phosphoregulation of microtubule-based motor proteins. While each pathway appears to affect FAT in a unique manner, in the context of AD, many of these pathways might work synergistically to compromise the delivery of molecular components critical for the maintenance and function of synapses and axons. Therapeutic approaches aimed at preventing FAT deficits by normalizing the activity of specific protein kinases may help prevent degeneration of vulnerable neurons in AD. PMID:22721767

Stress-Induced CDK5 Activation Disrupts Axonal Transport via Lis1/Ndel1/Dynein.

PubMed

Klinman, Eva; Holzbaur, Erika L F

2015-07-21

Axonal transport is essential for neuronal function, and defects in transport are associated with multiple neurodegenerative diseases. Aberrant cyclin-dependent kinase 5 (CDK5) activity, driven by the stress-induced activator p25, also is observed in these diseases. Here we show that elevated CDK5 activity increases the frequency of nonprocessive events for a range of organelles, including lysosomes, autophagosomes, mitochondria, and signaling endosomes. Transport disruption induced by aberrant CDK5 activation depends on the Lis1/Ndel1 complex, which directly regulates dynein activity. CDK5 phosphorylation of Ndel1 favors a high affinity Lis1/Ndel/dynein complex that blocks the ATP-dependent release of dynein from microtubules, inhibiting processive motility of dynein-driven cargo. Similar transport defects observed in neurons from a mouse model of amyotrophic lateral sclerosis are rescued by CDK5 inhibition. Together, these studies identify CDK5 as a Lis1/Ndel1-dependent regulator of transport in stressed neurons, and suggest that dysregulated CDK5 activity contributes to the transport deficits observed during neurodegeneration. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chlorpyrifos-Oxon Disrupts Zebrafish Axonal Growth and Motor Behavior

PubMed Central

Yang, Dongren; Lauridsen, Holly; Buels, Kalmia; Chi, Lai-Har; La Du, Jane; Bruun, Donald A.; Olson, James R.; Tanguay, Robert L.; Lein, Pamela J.

2011-01-01

Axonal morphology is a critical determinant of neuronal connectivity, and perturbation of the rate or extent of axonal growth during development has been linked to neurobehavioral deficits in animal models and humans. We previously demonstrated that the organophosphorus pesticide (OP) chlorpyrifos (CPF) inhibits axonal growth in cultured neurons. In this study, we used a zebrafish model to determine whether CPF, its oxon metabolite (CPFO), or the excreted metabolite trichloro-2-pyridinol (TCPy) alter spatiotemporal patterns of axonal growth in vivo. Static waterborne exposure to CPFO, but not CPF or TCPy, at concentrations ≥ 0.03μM from 24- to 72-h post fertilization significantly inhibited acetylcholinesterase, and high-performance liquid chromatography detected significantly more TCPy in zebrafish exposed to 0.1μM CPFO versus 1.0μM CPF. These data suggest that zebrafish lack the metabolic enzymes to activate CPF during these early developmental stages. Consistent with this, CPFO, but not CPF, significantly inhibited axonal growth of sensory neurons, primary motoneurons, and secondary motoneurons at concentrations ≥ 0.1μM. Secondary motoneurons were the most sensitive to axonal growth inhibition by CPFO, which was observed at concentrations that did not cause mortality, gross developmental defects, or aberrant somatic muscle differentiation. CPFO effects on axonal growth correlated with adverse effects on touch-induced swimming behavior, suggesting the functional relevance of these structural changes. These data suggest that altered patterns of neuronal connectivity contribute to the developmental neurotoxicity of CPF and demonstrate the relevance of zebrafish as a model for studying OP developmental neurotoxicity. PMID:21346248

Trafficking Mechanisms Underlying Neuronal Voltage-gated Ion Channel Localization at the Axon Initial Segment

PubMed Central

Vacher, Helene; Trimmer, James S.

2012-01-01

Summary Voltage-gated ion channels are diverse and fundamental determinants of neuronal intrinsic excitability. Voltage-gated K+ (Kv) and Na+ (Nav) channels play complex yet fundamentally important roles in determining intrinsic excitability. The Kv and Nav channels located at the axon initial segment (AIS) play a unique and especially important role in generating neuronal output in the form of anterograde axonal and backpropagating action potentials, Aberrant intrinsic excitability in individual neurons within networks contributes to synchronous neuronal activity leading to seizures. Mutations in ion channel genes gives rise to a variety of seizure-related “Channelopathies”, and many of the ion channel subunits associated with epilepsy mutations are localized at the AIS, making this a hotspot for epileptogenesis. Here we review the cellular mechanisms that underlie the trafficking of Kv and Nav channels found at the AIS, and how Kv and Nav channel mutations associated with epilepsy can alter these processes. PMID:23216576

Overexpression of mutant HSP27 causes axonal neuropathy in mice.

PubMed

Lee, Jinho; Jung, Sung-Chul; Joo, Jaesoon; Choi, Yu-Ri; Moon, Hyo Won; Kwak, Geon; Yeo, Ha Kyung; Lee, Ji-Su; Ahn, Hye-Jee; Jung, Namhee; Hwang, Sunhee; Rheey, Jingeun; Woo, So-Youn; Kim, Ji Yon; Hong, Young Bin; Choi, Byung-Ok

2015-06-19

Mutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) cause distal hereditary motor neuropathy (dHMN) or Charcot-Marie-Tooth disease type 2 F (CMT2F) according to unknown factors. Mutant HSP27 proteins affect axonal transport by reducing acetylated tubulin. We generated a transgenic mouse model overexpressing HSP27-S135F mutant protein driven by Cytomegalovirus (CMV) immediate early promoter. The mouse phenotype was similar to dHMN patients in that they exhibit motor neuropathy. To determine the phenotypic aberration of transgenic mice, behavior test, magnetic resonance imaging (MRI), electrophysiological study, and pathology were performed. Rotarod test showed that founder mice exhibited lowered motor performance. MRI also revealed marked fatty infiltration in the anterior and posterior compartments at calf level. Electrophysiologically, compound muscle action potential (CMAP) but not motor nerve conduction velocity (MNCV) was reduced in the transgenic mice. Toluidine staining with semi-thin section of sciatic nerve showed the ratio of large myelinated axon fiber was reduced, which might cause reduced locomotion in the transgenic mice. Electron microscopy also revealed abundant aberrant myelination. Immunohistochemically, neuronal dysfunctions included elevated level of phosphorylated neurofilament and reduced level of acetylated tubulin in the sural nerve of transgenic mice. There was no additional phenotype besides motor neuronal defects. Overexpression of HSP27-S135F protein causes peripheral neuropathy. The mouse model can be applied to future development of therapeutic strategies for dHMN or CMT2F.

An Allele of Sequoia Dominantly Enhances a Trio Mutant Phenotype to Influence Drosophila Larval Behavior

PubMed Central

Liebl, Eric C.

2013-01-01

The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency. PMID:24376789

An allele of sequoia dominantly enhances a trio mutant phenotype to influence Drosophila larval behavior.

PubMed

Dean, Kathryn E; Fields, April; Geer, Marcus J; King, Eric C; Lynch, Brian T; Manohar, Rohan R; McCall, Julianne R; Palozola, Katherine C; Zhang, Yan; Liebl, Eric C

2013-01-01

The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency.

Studying neuronal biomechanics and its role in CNS development

NASA Astrophysics Data System (ADS)

Franze, Kristian; Svoboda, Hanno; da F. Costa, Luciano; Guck, Jochen; Holt, Christine

2013-03-01

During the development of the nervous system, neurons migrate and grow over great distances. Currently, our understanding of nervous tissue development is, in large part, based on studies of biochemical signaling. Despite the fact that forces are involved in any kind of cell motion, mechanical aspects have so far rarely been considered. Here we used deformable cell culture substrates, traction force microscopy and calcium imaging to investigate how neurons probe and respond to their mechanical environment. While the growth rate of retinal ganglion cell axons was increased on stiffer substrates, their tendency to grow in bundles, which they show in vivo, was significantly enhanced on more compliant substrates. Moreover, if grown on substrates incorporating linear stiffness gradients, neuronal axons were repelled by stiff substrates. Mechanosensing involved the application of forces driven by the interaction of actin and myosin II, and the activation of stretch-activated ion channels leading to calcium influxes into the cells. Applying a modified atomic force microscopy techniquein vivo, we found mechanical gradients in developing brain tissue along which neurons grow. The application of chondroitin sulfate, which is a major extracellular matrix component in the developing brain, changed tissue mechanics and disrupted axonal pathfinding. Hence, our data suggest that neuronal growth is not only guided by chemical signals - as it is currently assumed - but also by the nervous tissue's mechanical properties.

Apical root canal transportation of different pathfinding systems and their effects on shaping ability of ProTaper Next

PubMed Central

Türker, Sevinç-Aktemur

2015-01-01

Background This study aimed to compare glide path preparation of different pathfinding systems and their effects on the apical transportation of ProTaper Next (Dentsply Maillefer, Ballaigues, Switzerland) in mesial root canals of extracted human mandibular molars, using digital subtraction radiography. Material and Methods The mesial canals of 40 mandibular first molars (with curvature angles between 25° and 35°) were selected for this study. The specimens were divided randomly into 4 groups with 10 canals each. Glide paths were created in group 1 with #10, #15 and #20 K-type (Dentsply Maillefer, Ballaigues, Switzerland) stainless steel manual files; in group 2 with Path-File (Dentsply Maillefer) #1, #2, and #3 and in group 3 with #16 ProGlider (Dentsply Maillefer) rotary instruments; in group 4 no glide paths were created. All canals were instrumented up to ProTaper Next X2 to the working length. A double digital radiograph technique was used, pre and post-instrumentation, to assess whether apical transportation and/or aberration in root canal morphology occurred. Instrument failures were also recorded. The data were analyzed statistically using ANOVA and Tukey tests (p<0.05). Results No significant differences were found among groups regarding apical transportation (p>0.05). Two ProTaper Next instruments failed in-group 4. Conclusions Within the parameters of this study, there was no difference between the performance of path-finding files and ProTaper Next system maintained root canal curvature well and was safe to use either with path-finding files or alone. Key words:Glide path, PathFile, ProGlider, ProTaper Next, transportation. PMID:26330936

Development of tactile sensory circuits in the CNS.

PubMed

Iwasato, Takuji; Erzurumlu, Reha S

2018-06-13

Molecular identification of neuronal types and genetic and imaging approaches to characterize their properties reveal morphological, physiological and dynamic aspects of sensory circuit development. Here we focus on the mouse tactile sensory circuitry, with particular emphasis on the main trigeminal pathway that connects the whiskers, the major tactile organ in rodents, to the neocortex. At each level of this pathway, neurogenesis, axonal elongation, pathfinding, target recognition and circuit reorganization including dendritic refinement of cortical layer 4 neurons occur contemporaneously and a multitude of molecular signals are used in differing combinations. We highlight recent advances in development of tactile circuitry and note gaps in our understanding. Copyright © 2018 Elsevier Ltd. All rights reserved.

Prevention of posttraumatic axon sprouting by blocking CRMP2-mediated neurite outgrowth and tubulin polymerization

PubMed Central

Wilson, Sarah M.; Xiong, Wenhui; Wang, Yuying; Ping, Xingjie; Head, Jessica D.; Brittain, Joel M.; Gagare, Pravin D.; Ramachandran, P. Veeraraghavan; Jin, Xiaoming; Khanna, Rajesh

2012-01-01

Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide (LCM) which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ~8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison to injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM’s mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting. PMID:22433297

Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

PubMed Central

Sharma, Swarkar; Gao, Xiaochong; Londono, Douglas; Devroy, Shonn E.; Mauldin, Kristen N.; Frankel, Jessica T.; Brandon, January M.; Zhang, Dongping; Li, Quan-Zhen; Dobbs, Matthew B.; Gurnett, Christina A.; Grant, Struan F.A.; Hakonarson, Hakon; Dormans, John P.; Herring, John A.; Gordon, Derek; Wise, Carol A.

2011-01-01

Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10−8 for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case–control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29–1.73, P = 2.58 × 10−8), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease. PMID:21216876

Aurora kinase B regulates axonal outgrowth and regeneration in the spinal motor neurons of developing zebrafish.

PubMed

Gwee, Serene S L; Radford, Rowan A W; Chow, Sharron; Syal, Monisha D; Morsch, Marco; Formella, Isabel; Lee, Albert; Don, Emily K; Badrock, Andrew P; Cole, Nicholas J; West, Adrian K; Cheung, Steve N S; Chung, Roger S

2018-02-21

Aurora kinase B (AurkB) is a serine/threonine protein kinase with a well-characterised role in orchestrating cell division and cytokinesis, and is prominently expressed in healthy proliferating and cancerous cells. However, the role of AurkB in differentiated and non-dividing cells has not been extensively explored. Previously, we have described a significant upregulation of AurkB expression in cultured cortical neurons following an experimental axonal transection. This is somewhat surprising, as AurkB expression is generally associated only with dividing cells Frangini et al. (Mol Cell 51:647-661, 2013); Hegarat et al. (J Cell Biol 195:1103-1113, 2011); Lu et al. (J Biol Chem 283:31785-31790, 2008); Trakala et al. (Cell Cycle 12:1030-1041, 2014). Herein, we present the first description of a role for AurkB in terminally differentiated neurons. AurkB was prominently expressed within post-mitotic neurons of the zebrafish brain and spinal cord. The expression of AurkB varied during the development of the zebrafish spinal motor neurons. Utilising pharmacological and genetic manipulation to impair AurkB activity resulted in truncation and aberrant motor axon morphology, while overexpression of AurkB resulted in extended axonal outgrowth. Further pharmacological inhibition of AurkB activity in regenerating axons delayed their recovery following UV laser-mediated injury. Collectively, these results suggest a hitherto unreported role of AurkB in regulating neuronal development and axonal outgrowth.

Pyramidal tract stimulation restores normal corticospinal tract connections and visuomotor skill after early postnatal motor cortex activity blockade

PubMed Central

Salimi, I; Friel, KM; Martin, JH

2008-01-01

Motor development depends on forming specific connections between the corticospinal tract (CST) and the spinal cord. Blocking CST activity in kittens during the critical period for establishing connections with spinal motor circuits results in permanent impairments in connectivity and function. The changes in connections are consistent with the hypothesis that the inactive tract is less competitive in developing spinal connections than the active tract. In this study we tested the competition hypothesis by determining if activating CST axons, after prior silencing during the critical period, abrogated development of aberrant corticospinal connections and motor impairments. In kittens, we inactivated motor cortex by muscimol infusion between postnatal weeks 5-7. We next electrically stimulated CST axons in the medullary pyramid 2.5 hours daily, between weeks 7-10. In controls (n=3), CST terminations were densest within the contralateral deeper, premotor, spinal layers. After prior inactivation (n=3), CST terminations were densest within the dorsal, somatic sensory, layers. There were more ipsilateral terminations from the active tract. During visually guided locomotion, there was a movement endpoint impairment. Stimulation after inactivation (n=6) resulted in significantly fewer terminations in the sensory layers and more in the premotor layers, and fewer ipsilateral connections from active cortex. Chronic stimulation reduced the current threshold for evoking contralateral movements by pyramidal stimulation, suggesting strengthening of connections. Importantly, stimulation significantly improved stepping accuracy. These findings show the importance of activity-dependent processes in specifying CST connections. They also provide a strategy for harnessing activity to rescue CST axons at risk of developing aberrant connections after CNS injury. PMID:18632946

Roles of specific membrane lipid domains in EGF receptor activation and cell adhesion molecule stabilization in a developing olfactory system.

PubMed

Gibson, Nicholas J; Tolbert, Leslie P; Oland, Lynne A

2009-09-29

Reciprocal interactions between glial cells and olfactory receptor neurons (ORNs) cause ORN axons entering the brain to sort, to fasciculate into bundles destined for specific glomeruli, and to form stable protoglomeruli in the developing olfactory system of an experimentally advantageous animal species, the moth Manduca sexta. Epidermal growth factor receptors (EGFRs) and the cell adhesion molecules (IgCAMs) neuroglian and fasciclin II are known to be important players in these processes. We report in situ and cell-culture studies that suggest a role for glycosphingolipid-rich membrane subdomains in neuron-glia interactions. Disruption of these subdomains by the use of methyl-beta-cyclodextrin results in loss of EGFR activation, depletion of fasciclin II in ORN axons, and loss of neuroglian stabilization in the membrane. At the cellular level, disruption leads to aberrant ORN axon trajectories, small antennal lobes, abnormal arrays of olfactory glomerul, and loss of normal glial cell migration. We propose that glycosphingolipid-rich membrane subdomains (possible membrane rafts or platforms) are essential for IgCAM-mediated EGFR activation and for anchoring of neuroglian to the cytoskeleton, both required for normal extension and sorting of ORN axons.

Roles of Specific Membrane Lipid Domains in EGF Receptor Activation and Cell Adhesion Molecule Stabilization in a Developing Olfactory System

PubMed Central

Gibson, Nicholas J.; Tolbert, Leslie P.; Oland, Lynne A.

2009-01-01

Background Reciprocal interactions between glial cells and olfactory receptor neurons (ORNs) cause ORN axons entering the brain to sort, to fasciculate into bundles destined for specific glomeruli, and to form stable protoglomeruli in the developing olfactory system of an experimentally advantageous animal species, the moth Manduca sexta. Epidermal growth factor receptors (EGFRs) and the cell adhesion molecules (IgCAMs) neuroglian and fasciclin II are known to be important players in these processes. Methodology/Principal Findings We report in situ and cell-culture studies that suggest a role for glycosphingolipid-rich membrane subdomains in neuron-glia interactions. Disruption of these subdomains by the use of methyl-β-cyclodextrin results in loss of EGFR activation, depletion of fasciclin II in ORN axons, and loss of neuroglian stabilization in the membrane. At the cellular level, disruption leads to aberrant ORN axon trajectories, small antennal lobes, abnormal arrays of olfactory glomerul, and loss of normal glial cell migration. Conclusions/Significance We propose that glycosphingolipid-rich membrane subdomains (possible membrane rafts or platforms) are essential for IgCAM-mediated EGFR activation and for anchoring of neuroglian to the cytoskeleton, both required for normal extension and sorting of ORN axons. PMID:19787046

Drosophila Activin- and the Activin-like product Dawdle function redundantly to regulate proliferation in the larval brain.

PubMed

Zhu, Changqi C; Boone, Jason Q; Jensen, Philip A; Hanna, Scott; Podemski, Lynn; Locke, John; Doe, Chris Q; O'Connor, Michael B

2008-02-01

The Drosophila Activin-like ligands Activin-beta and Dawdle control several aspects of neuronal morphogenesis, including mushroom body remodeling, dorsal neuron morphogenesis and motoneuron axon guidance. Here we show that the same two ligands act redundantly through the Activin receptor Babo and its transcriptional mediator Smad2 (Smox), to regulate neuroblast numbers and proliferation rates in the developing larval brain. Blocking this pathway results in the development of larvae with small brains and aberrant photoreceptor axon targeting, and restoring babo function in neuroblasts rescued these mutant phenotypes. These results suggest that the Activin signaling pathway is required for producing the proper number of neurons to enable normal connection of incoming photoreceptor axons to their targets. Furthermore, as the Activin pathway plays a key role in regulating propagation of mouse and human embryonic stem cells, our observation that it also regulates neuroblast numbers and proliferation in Drosophila suggests that involvement of Activins in controlling stem cell propagation may be a common regulatory feature of this family of TGF-beta-type ligands.

Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders.

PubMed

Inaguma, Yutaka; Matsumoto, Ayumi; Noda, Mariko; Tabata, Hidenori; Maeda, Akihiko; Goto, Masahide; Usui, Daisuke; Jimbo, Eriko F; Kikkawa, Kiyoshi; Ohtsuki, Mamitaro; Momoi, Mariko Y; Osaka, Hitoshi; Yamagata, Takanori; Nagata, Koh-Ichi

2016-10-01

Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis. Time-lapse imaging revealed that the abnormal positioning was at least partially because of the reduced migration velocity. When PIK3C3 was silenced in cortical neurons in one hemisphere, axon extension to the contralateral hemisphere was also delayed. These aberrant phenotypes were rescued by RNAi-resistant PIK3C3. Notably, knockdown of PIK3C3 did not affect the cell cycle of neuronal progenitors and stem cells at the ventricular zone. Taken together, PIK3C3 was thought to play a crucial role in corticogenesis through the regulation of excitatory neuron migration and axon extension. Meanwhile, when we performed comparative genomic hybridization on a patient with specific learning disorders, a 107 Kb-deletion was identified on 18q12.3 (nt. 39554147-39661206) that encompasses exons 5-23 of PIK3C3. Notably, the above aberrant migration and axon growth phenotypes were not rescued by the disease-related truncation mutant (172 amino acids) lacking the C-terminal kinase domain. Thus, functional defects of PIK3C3 might impair corticogenesis and relate to the pathophysiology of specific learning disorders and other neurodevelopmental disorders. Acute knockdown of Class III phosphoinositide 3-kinase (PIK3C3) evokes migration defects of excitatory neurons during corticogenesis. PIK3C3-knockdown also disrupts axon outgrowth, but not progenitor proliferation in vivo. Involvement of PIK3C3 in neurodevelopmental disorders might be an interesting future subject since a deletion mutation in PIK3C3 was detected in a patient with specific learning disorders (SLD). © 2016 International Society for Neurochemistry.

Spontaneous regeneration of the corticospinal tract after transection in young rats: a key role of reactive astrocytes in making favorable and unfavorable conditions for regeneration.

PubMed

Iseda, T; Nishio, T; Kawaguchi, S; Yamanoto, M; Kawasaki, T; Wakisaka, S

2004-01-01

We demonstrated the occurrence of marked regeneration of the corticospinal tract (CST) after a single transection and failure of regeneration after a repeated transection in young rats. To provide convincing evidence for the complete transection and regeneration we used retrograde neuronal double labeling. Double-labeled neurons that took up the first tracer from the transection site and the second tracer from the injection site caudal to the transection site were observed in the sensorimotor cortex. The anterograde tracing method revealed various patterns of regeneration. In the most successful cases the vast majority of regenerated fibers descended in the normal tract and terminated normally whereas a trace amount of fibers coursed aberrantly. In the less successful cases fibers descended partly normally and partly aberrantly or totally aberrantly. To clarify the role of astrocytes in determining the success or failure of regeneration we compared expression of glial fibrillary acidic protein (GFAP), vimentin and neurofilament (NF) immunoreactivity (IR) in the lesion between single and repeated transections. In either transection, astrocytes disappeared from the CST near the lesion site as early as 3 h after lesioning. However, by 24 h after a single transection, immature astrocytes coexpressing GFAP- and vimentin-IR appeared in the former astrocyte-free area and NF-positive axons crossed the lesion. By contrast, after a repeated transection the astrocyte-free area spread and NF-positive axons never crossed the lesion. It appears likely that the major sign, and possibly cause of failure of regeneration is the prolonged disappearance of astrocytes in the lesioned tract area. Copyright 2004 IBRO

A Reorganized GABAergic Circuit in a Model of Epilepsy: Evidence from Optogenetic Labeling and Stimulation of Somatostatin Interneurons

PubMed Central

Peng, Zechun; Zhang, Nianhui; Wei, Weizheng; Huang, Christine S.; Cetina, Yliana; Otis, Thomas S.

2013-01-01

Axonal sprouting of excitatory neurons is frequently observed in temporal lobe epilepsy, but the extent to which inhibitory interneurons undergo similar axonal reorganization remains unclear. The goal of this study was to determine whether somatostatin (SOM)-expressing neurons in stratum (s.) oriens of the hippocampus exhibit axonal sprouting beyond their normal territory and innervate granule cells of the dentate gyrus in a pilocarpine model of epilepsy. To obtain selective labeling of SOM-expressing neurons in s. oriens, a Cre recombinase-dependent construct for channelrhodopsin2 fused to enhanced yellow fluorescent protein (ChR2-eYFP) was virally delivered to this region in SOM-Cre mice. In control mice, labeled axons were restricted primarily to s. lacunosum-moleculare. However, in pilocarpine-treated animals, a rich plexus of ChR2-eYFP-labeled fibers and boutons extended into the dentate molecular layer. Electron microscopy with immunogold labeling demonstrated labeled axon terminals that formed symmetric synapses on dendritic profiles in this region, consistent with innervation of granule cells. Patterned illumination of ChR2-labeled fibers in s. lacunosum-moleculare of CA1 and the dentate molecular layer elicited GABAergic inhibitory responses in dentate granule cells in pilocarpine-treated mice but not in controls. Similar optical stimulation in the dentate hilus evoked no significant responses in granule cells of either group of mice. These findings indicate that under pathological conditions, SOM/GABAergic neurons can undergo substantial axonal reorganization beyond their normal territory and establish aberrant synaptic connections. Such reorganized circuitry could contribute to functional deficits in inhibition in epilepsy, despite the presence of numerous GABAergic terminals in the region. PMID:24005292

Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

PubMed Central

Gassman, Andrew; Hao, Le T.; Bhoite, Leena; Bradford, Chad L.; Chien, Chi-Bin; Beattie, Christine E.; Manfredi, John P.

2013-01-01

Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease. PMID:24023935

Dscam1-mediated self-avoidance counters netrin-dependent targeting of dendrites in Drosophila.

PubMed

Matthews, Benjamin J; Grueber, Wesley B

2011-09-13

Dendrites and axons show precise targeting and spacing patterns for proper reception and transmission of information in the nervous system. Self-avoidance promotes complete territory coverage and nonoverlapping spacing between processes from the same cell [1, 2]. Neurons that lack Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) show aberrant overlap, fasciculation, and accumulation of dendrites and axons, demonstrating a role in self-recognition and repulsion leading to self-avoidance [3-11]. Fasciculation and accumulation of processes suggested that Dscam1 might promote process spacing by counterbalancing developmental signals that otherwise promote self-association [9, 12]. Here we show that Dscam1 functions to counter Drosophila sensory neuron dendritic targeting signals provided by secreted Netrin-B and Frazzled, a netrin receptor. Loss of Dscam1 function resulted in aberrant dendrite accumulation at a Netrin-B-expressing target, whereas concomitant loss of Frazzled prevented accumulation and caused severe deficits in dendritic territory coverage. Netrin misexpression was sufficient to induce ectopic dendritic targeting in a Frazzled-dependent manner, whereas Dscam1 was required to prevent ectopic accumulation, consistent with separable roles for these receptors. Our results suggest that Dscam1-mediated self-avoidance counters extrinsic signals that are required for normal dendritic patterning, but whose action would otherwise favor neurite accumulation. Counterbalancing roles for Dscam1 may be deployed in diverse contexts during neural circuit formation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dscam1-mediated self-avoidance counters Netrin-dependent targeting of dendrites in Drosophila

PubMed Central

Matthews, Benjamin J.; Grueber, Wesley B.

2011-01-01

SUMMARY Dendrites and axons show precise targeting and spacing patterns for proper reception and transmission of information in the nervous system. Self-avoidance promotes complete territory coverage and non-overlapping spacing between processes from the same cell [1, 2]. Neurons that lack Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) show aberrant overlap, fasciculation, and accumulation of dendrites and axons, demonstrating a role in self-recognition and repulsion leading to self-avoidance [3–11]. Fasciculation and accumulation of processes suggested that Dscam1 might promote process spacing by counterbalancing developmental signals that otherwise promote self-association [9, 12]. Here we show that Dscam1 functions to counter sensory neuron dendritic targeting signals provided by secreted Netrin-B and Frazzled, a netrin receptor. Loss of Dscam1 function resulted in aberrant dendrite accumulation at a Netrin-B expressing target, whereas concomitant loss of Frazzled prevented accumulation and caused severe deficits in dendritic territory coverage. Netrin misexpression was sufficient to induce ectopic dendritic targeting in a Frazzled-dependent manner, whereas Dscam1 was required to prevent ectopic accumulation, consistent with separable roles for these receptors. Our results suggest that Dscam1-mediated self-avoidance counter extrinsic signals that are required for normal dendritic patterning, but whose action would otherwise favor neurite accumulation. Counterbalancing roles for Dscam1 may be deployed in diverse contexts during neural circuit formation. PMID:21871804

Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.

PubMed

De Gregorio, Cristian; Delgado, Ricardo; Ibacache, Andrés; Sierralta, Jimena; Couve, Andrés

2017-10-15

Hereditary spastic paraplegias (HSPs) are characterized by spasticity and weakness of the lower limbs, resulting from length-dependent axonopathy of the corticospinal tracts. In humans, the HSP-related atlastin genes ATL1 - ATL3 catalyze homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using Drosophila , we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability. Broad expression in the nervous system is required to rescue the atlastin -null Drosophila mutant ( atl 2 ) phenotype. Importantly, both spontaneous release and the reserve pool of synaptic vesicles are affected. Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, possibly in lysosomes. Our findings suggest that trafficking defects produced by Atlastin dysfunction in motor neurons result in redistribution of presynaptic components and aberrant mobilization of synaptic vesicles, stressing the importance of ER-shaping proteins and the susceptibility of motor neurons to their mutations or depletion. © 2017. Published by The Company of Biologists Ltd.

Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels.

PubMed

Kagitani-Shimono, Kuriko; Mohri, Ikuko; Yagi, Takashi; Taniike, Masako; Suzuki, Kinuko

2008-05-01

Globoid cell leukodystrophy (GLD; Krabbe's disease), caused by a genetic galactosylceramidase deficiency, affects both the central and peripheral nervous systems (CNS and PNS). Allogenic hematopoietic stem-cell transplantation (HSCT) has been beneficial for clinical improvement of this disease. However, recent reports by Siddiqi et al. suggested that none of their transplanted patients achieved complete normalization of their peripheral nerve function, despite the well-documented remyelination of the CNS and PNS in the treated patients. We hypothesized that the PNS dysfunction in GLD is due to altered Schwann cell-axon interactions, resulting in structural abnormalities of the node of Ranvier and aberrant expression of ion channels caused by demyelination and that the persistence of this altered interaction is responsible for the dysfunction of the PNS after HSCT. Since there has not been any investigation of the Schwann cell-axonal relationship in twitcher mice, an authentic model of GLD, we first investigated structural abnormalities, focusing on the node of Ranvier in untreated twitcher mice, and compared the results with those obtained after receiving bone marrow transplantation (BMT). As expected, we found numerous supernumerary Schwann cells that formed structurally abnormal nodes of Ranvier. Similar findings, though at somewhat variable extent, were detected in mice treated with BMT. Activated supernumerary Schwann cells expressed GFAP immunoreactivity and generated Alcian blue-positive extracellular matrix (ECM) in the endoneurial space. The processes of these supernumerary Schwann cells often covered and obliterated the nodal regions. Furthermore, the distribution of Na(+) channel immunoreactivity was diffuse without the concentration at the nodes of Ranvier as seen in wild-type mice. Neither K(+) channels nor Neurexin IV/ Caspr/ Paranoidin (NCP-1) were detected in the twi/twi sciatic nerve. The results of our study suggest the importance of normalization of the Schwann cell-axon relationship for the functional recovery of peripheral nerves, when one considers therapeutic strategies for PNS pathology in GLD.

Morphological and functional changes in TRPM8-expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice.

PubMed

Alcalde, Ignacio; Íñigo-Portugués, Almudena; González-González, Omar; Almaraz, Laura; Artime, Enol; Morenilla-Palao, Cruz; Gallar, Juana; Viana, Félix; Merayo-Lloves, Jesús; Belmonte, Carlos

2018-08-01

Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8 BAC -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8 + corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8 + corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people. © 2018 Wiley Periodicals, Inc.

β3GnT2 Maintains Adenylyl Cyclase-3 Signaling and Axon Guidance Molecule Expression in the Olfactory Epithelium

PubMed Central

Faden, Ashley A.; Knott, Thomas K.

2011-01-01

In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase β3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function. We show here that AC3 is extensively modified with N-linked PLN, which is essential for AC3 activity and localization. On Western blots, AC3 from the wild-type OE migrates diffusely as a heavily glycosylated 200 kDa band that interacts with the PLN-binding lectin LEA. AC3 from the β3GnT2−/− OE loses these PLN modifications, migrating instead as a 140 kDa glycoprotein. Furthermore, basal and forskolin-stimulated cAMP production is reduced 80–90% in the β3GnT2−/− OE. Although AC3 traffics normally to null OSN cilia, it is absent from axon projections that aberrantly target the OB. The cAMP-dependent guidance receptor neuropilin-1 is also lost from β3GnT2−/− OSNs and axons, while semaphorin-3A ligand expression is upregulated. In addition, kirrel2, a mosaically expressed adhesion molecule that functions in axon sorting, is absent from β3GnT2−/− OB projections. These results demonstrate that PLN glycans are essential in OSNs for proper AC3 localization and function. We propose that the loss of cAMP-dependent guidance cues is also a critical factor in the severe axon guidance defects observed in β3GnT2−/− mice. PMID:21525298

Alterations of Hippocampal Myelin Sheath and Axon Sprouting by Status Convulsion and Regulating Lingo-1 Expression with RNA Interference in Immature and Adult Rats.

PubMed

Song, Xiao-Jie; Han, Wei; He, Rong; Li, Tian-Yi; Xie, Ling-Ling; Cheng, Li; Chen, Heng-Sheng; Jiang, Li

2018-03-01

Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent characteristics of myelinated fiber injury induced by seizures. Considering the critical functions of oligodendrocyte progenitor cells (OPCs) in myelination and Lingo-1 signaling in regulating OPCs' differentiation, the present study aimed to explore the effects of Lingo-1 on myelin and axon in immature and adult rats after status convulsion (SC) induced by lithium-pilocarpine, and the differences between immature and adult brains. Dynamic variations in electrophysiological activity and spontaneous recurrent seizures were recorded by electroencephalogram monitoring after SC. The impaired microstructures of myelin sheaths and decrease in myelin basic protein caused by SC were observed through transmission electron microscopy and western blot analysis respectively, which became more severe in adult rats, but improved gradually in immature rats. Aberrant axon sprouting occurred in adult rats, which was more prominent than in immature rats, as shown by a Timm stain. This damage was improved or negatively affected after down or upregulating Lingo-1 expression. These results demonstrated that in both immature and adult brains, Lingo-1 signaling plays important roles in seizure-induced damage to myelin sheaths and axon growth. The plasticity of the developing brain may provide a potential window of opportunity to prevent the brain from damage.

BMP7 and SHH regulate Pax2 in mouse retinal astrocytes by relieving TLX repression.

PubMed

Sehgal, Rachna; Sheibani, Nader; Rhodes, Simon J; Belecky Adams, Teri L

2009-08-15

Pax2 is essential for development of the neural tube, urogenital system, optic vesicle, optic cup and optic tract. In the eye, Pax2 deficiency is associated with coloboma, a loss of astrocytes in the optic nerve and retina, and abnormal axonal pathfinding of the ganglion cell axons at the optic chiasm. Thus, appropriate expression of Pax2 is essential for astrocyte determination and differentiation. Although BMP7 and SHH have been shown to regulate Pax2 expression, the molecular mechanism by which this regulation occurs is not well understood. In this study, we determined that BMP7 and SHH activate Pax2 expression in mouse retinal astrocyte precursors in vitro. SHH appeared to play a dual role in Pax2 regulation; 1) SHH may regulate BMP7 expression, and 2) the SHH pathway cooperates with the BMP pathway to regulate Pax2 expression. BMP and SHH pathway members can interact separately or together with TLX, a repressor protein in the tailless transcription factor family. Here we show that the interaction of both pathways with TLX relieves the repression of Pax2 expression in mouse retinal astrocytes. Together these data reveal a new mechanism for the cooperative actions of signaling pathways in astrocyte determination and differentiation and suggest interactions of regulatory pathways that are applicable to other developmental programs.

Decoding spatial and temporal features of neuronal cAMP/PKA signaling with FRET biosensors.

PubMed

Castro, Liliana R V; Guiot, Elvire; Polito, Marina; Paupardin-Tritsch, Daniéle; Vincent, Pierre

2014-02-01

Cyclic adenosine monophosphate (cAMP) and the cyclic-AMP-dependent protein kinase (PKA) regulate a plethora of cellular functions in virtually all eukaryotic cells. In neurons, the cAMP/PKA signaling cascade controls a number of biological properties such as axonal growth, pathfinding, efficacy of synaptic transmission, regulation of excitability, or long term changes. Genetically encoded optical biosensors for cAMP or PKA are considerably improving our understanding of these processes by providing a real-time measurement in living neurons. In this review, we describe the recent progress made in the creation of biosensors for cAMP or PKA activity. These biosensors revealed profound differences in the amplitude of the cAMP signal evoked by neuromodulators between various neuronal preparations. These responses can be resolved at the level of individual neurons, also revealing differences related to the neuronal type. At the sub-cellular level, biosensors reported different signal dynamics in domains like dendrites, cell body, nucleus, and axon. Combining this imaging approach with pharmacology or genetic models points at phosphodiesterases and phosphatases as critical regulatory proteins. Biosensor imaging will certainly emerge as a forefront tool to decipher the subtle mechanics of intracellular signaling. This will certainly help us to understand the mechanism of action of current drugs and foster the development of novel molecules for neuropsychiatric diseases. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Extracellular matrix and its receptors in Drosophila neural development

PubMed Central

Broadie, Kendal; Baumgartner, Stefan; Prokop, Andreas

2011-01-01

Extracellular matrix (ECM) and matrix receptors are intimately involved in most biological processes. The ECM plays fundamental developmental and physiological roles in health and disease, including processes underlying the development, maintenance and regeneration of the nervous system. To understand the principles of ECM-mediated functions in the nervous system, genetic model organisms like Drosophila provide simple, malleable and powerful experimental platforms. This article provides an overview of ECM proteins and receptors in Drosophila. It then focuses on their roles during three progressive phases of neural development: 1) neural progenitor proliferation, 2) axonal growth and pathfinding and 3) synapse formation and function. Each section highlights known ECM and ECM-receptor components and recent studies done in mutant conditions to reveal their in vivo functions, all illustrating the enormous opportunities provided when merging work on the nervous system with systematic research into ECM-related gene functions. PMID:21688401

Serpins Promote Cancer Cell Survival and Vascular Cooption in Brain Metastasis

PubMed Central

Valiente, Manuel; Obenauf, Anna C.; Jin, Xin; Chen, Qing; Zhang, Xiang H.-F.; Lee, Derek J.; Chaft, Jamie E.; Kris, Mark G.; Huse, Jason T.; Brogi, Edi; Massagué, Joan

2014-01-01

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM that metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its deleterious consequences. By protecting cancer cells from death signals and fostering vascular cooption, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers. PMID:24581498

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

PubMed Central

Nguyen, Tammy T.; Oh, Sang S.; Weaver, David; Lewandowska, Agnieszka; Maxfield, Dane; Schuler, Max-Hinderk; Smith, Nathan K.; Macfarlane, Jane; Saunders, Gerald; Palmer, Cheryl A.; Debattisti, Valentina; Koshiba, Takumi; Pulst, Stefan; Feldman, Eva L.; Hajnóczky, György; Shaw, Janet M.

2014-01-01

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease. PMID:25136135

Pathfinder-Plus takes off on flight in Hawaii

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on a flight over Hawaii in 1998. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight in Hawaii

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on a flight over Hawaii in 1998. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on a flight over Hawaiian island N'ihau

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on a flight over the Hawaiian island of N'ihau in 1998. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight over Hawaiian island N'ihau

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on a flight over the Hawaiian island of N'ihau in 1998. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight near Hawaiian island N'ihau

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on a flight with the Hawaiian island of N'ihau in the background. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight over Hawaii

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus flying over the Hawaiian Islands in 1998 with Ni'ihau Island in the background. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight over Hawaii

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on flight over Hawaii. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on a flight in Hawaii

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on a flight in 1998 over Hawaiian waters. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight over Hawaiian Islands

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on flight over Hawaiian Islands in 1998. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

Pathfinder-Plus on flight over Hawaiian Islands, with N'ihau and Lehua in the background

NASA Technical Reports Server (NTRS)

1998-01-01

Pathfinder-Plus on flight over Hawaiian Islands, with N'ihau and Lehua in the background. Pathfinder was a remotely controlled, solar-powered flying wing, designed and built as a proof-of-concept vehicle for a much larger aircraft capable of flying at extremely high altitudes for weeks at a time. It was built by AeroVironment, Inc., a California company that developed the human-powered Gossamer Condor and Gossamer Albatross lightweight aircraft during the 1970s, and later made the solar-electric powered Gossamer Penguin and Solar Challenger. The basic configuration and concepts for Pathfinder were first realized with the HALSOL (High Altitude Solar) aircraft, built in 1983 by AeroVironment and the Lawrence Livermore Laboratory. Pathfinder was constructed of advanced composites, plastics, and foam, and despite a wingspan of nearly 100 feet, it weighed only about 600 pounds. Pathfinder was one of several unpiloted prototypes under study by NASA's ERAST (Environmental Research Aircraft and Sensor Technology) program, a NASA-industry alliance which is helping develop advanced technologies that will enable aircraft to study the earth's environment during extremely long flights at altitudes in excess of 100,000 feet. (See project description below for Pathfinder's conversion to Pathfinder Plus.) In 1998, the Pathfinder solar-powered flying wing (see its photographs and project description) was modified into the longer-winged Pathfinder Plus configuration and on Aug. 6, 1998, Pathfinder Plus set an altitude record (for propeller-driven aircraft) of approximately 80,285 feet at the Pacific Missile Range Facility. The goal of the Pathfinder Plus flights was to validate new solar, aerodynamic, propulsion, and systems technology developed for its successor, the Centurion, which was designed to reach and sustain altitudes in the 100,000-foot range. The Centurion was succeeded by the Helios Prototype with a goal of reaching and sustaining flight at an altitude of 100,000 feet and flying non-stop for at least 4 days above 50,000 feet. Major activities of Pathfinder Plus' Hawaiian flights included detection of forest nutrient status, forest regrowth after damage caused by Hurricane Iniki in 1992, sediment/algal concentrations in coastal waters, and assessment of coral reef health. Pathfinder science activities were coordinated by NASA's Ames Research Center, Mountain View, California, and included researchers from the University of Hawaii and the University of California. Pathfinder is part of NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program managed by NASA's Dryden Flight Research Center, Edwards, California. Pathfinder and Pathfinder Plus were designed, built, and operated by AeroVironment, Inc., Monrovia, California. Pathfinder had a 98.4-foot wing span and weighed 560 pounds. Pathfinder Plus has a 121-foot wing span and weighs about 700 pounds. Pathfinder was powered by six electric motors while Pathfinder Plus has eight. Pathfinder's solar arrays produced approximately 8,000 watts of power while Pathfinder Plus' solar arrays produce about 12,500 watts of power. Both Pathfinder aircraft were built primarily of composites, plastic, and foam.

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders.

PubMed

Gennarini, Gianfranco; Bizzoca, Antonella; Picocci, Sabrina; Puzzo, Daniela; Corsi, Patrizia; Furley, Andrew J W

2017-06-01

This review article focuses on the Contactin (CNTN) subset of the Immunoglobulin supergene family (IgC2/FNIII molecules), whose components share structural properties (the association of Immunoglobulin type C2 with Fibronectin type III domains), as well as a general role in cell contact formation and axonal growth control. IgC2/FNIII molecules include 6 highly related components (CNTN 1-6), associated with the cell membrane via a Glycosyl Phosphatidyl Inositol (GPI)-containing lipid tail. Contactin 1 and Contactin 2 share ~50 (49.38)% identity at the aminoacid level. They are components of the cell surface, from which they may be released in soluble forms. They bind heterophilically to multiple partners in cis and in trans, including members of the related L1CAM family and of the Neurexin family Contactin-associated proteins (CNTNAPs or Casprs). Such interactions are important for organising the neuronal membrane, as well as for modulating the growth and pathfinding of axon tracts. In addition, they also mediate the functional maturation of axons by promoting their interactions with myelinating cells at the nodal, paranodal and juxtaparanodal regions. Such interactions also mediate differential ionic channels (both Na + and K + ) distribution, which is of critical relevance in the generation of the peak-shaped action potential. Indeed, thanks to their interactions with Ankyrin G, Na + channels map within the nodal regions, where they drive axonal depolarization. However, no ionic channels are found in the flanking Contactin1-containing paranodal regions, where CNTN1 interactions with Caspr1 and with the Ig superfamily component Neurofascin 155 in cis and in trans, respectively, build a molecular barrier between the node and the juxtaparanode. In this region K + channels are clustered, depending upon molecular interactions with Contactin 2 and with Caspr2. In addition to these functions, the Contactins appear to have also a role in degenerative and inflammatory disorders: indeed Contactin 2 is involved in neurodegenerative disorders with a special reference to the Alzheimer disease, given its ability to work as a ligand of the Alzheimer Precursor Protein (APP), which results in increased Alzheimer Intracellular Domain (AICD) release in a γ-secretase-dependent manner. On the other hand Contactin 1 drives Notch signalling activation via the Hes pathway, which could be consistent with its ability to modulate neuroinflammation events, and with the possibility that Contactin 1-dependent interactions may participate to the pathogenesis of the Multiple Sclerosis and of other inflammatory disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats.

PubMed

Akude, Eli; Zherebitskaya, Elena; Chowdhury, Subir K Roy; Smith, Darrell R; Dobrowsky, Rick T; Fernyhough, Paul

2011-01-01

Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.

Neuroprotective Effects of Transcription Factor Brn3b in an Ocular Hypertension Rat Model of Glaucoma

PubMed Central

Stankowska, Dorota L.; Minton, Alena Z.; Rutledge, Margaret A.; Mueller, Brett H.; Phatak, Nitasha R.; He, Shaoqing; Ma, Hai-Ying; Forster, Michael J.; Yorio, Thomas; Krishnamoorthy, Raghu R.

2015-01-01

Purpose. Glaucoma is an optic neuropathy commonly associated with elevated intraocular pressure (IOP), leading to optic nerve head (ONH) cupping, axon loss, and apoptosis of retinal ganglion cells (RGCs), which could ultimately result in blindness. Brn3b is a class-4 POU domain transcription factor that plays a key role in RGC development, axon outgrowth, and pathfinding. Previous studies suggest that a decrease in Brn3b levels occurs in animal models of glaucoma. The goal of this study was to determine if adeno-associated virus (AAV)-directed overexpression of the Brn3b protein could have neuroprotective effects following elevated IOP-mediated neurodegeneration. Methods. Intraocular pressure was elevated in one eye of Brown Norway rats (Rattus norvegicus), following which the IOP-elevated eyes were intravitreally injected with AAV constructs encoding either the GFP (rAAV-CMV-GFP and rAAV-hsyn-GFP) or Brn3b (rAAV-CMV-Brn3b and rAAV-hsyn-Brn3b). Retina sections through the ONH were stained for synaptic plasticity markers and neuroprotection was assessed by RGC counts and visual acuity tests. Results. Adeno-associated virus–mediated expression of the Brn3b protein in IOP-elevated rat eyes promoted an upregulation of growth associated protein-43 (GAP-43), actin binding LIM protein (abLIM) and acetylated α-tubulin (ac-Tuba) both posterior to the ONH and in RGCs. The RGC survival as well as axon integrity score were significantly improved in IOP-elevated rAAV-hsyn-Brn3b–injected rats compared with those of the IOP-elevated rAAV-hsyn-GFP– injected rats. Additionally, intravitreal rAAV-hsyn-Brn3b administration significantly restored the visual optomotor response in IOP-elevated rat eyes. Conclusions. Adeno-associated virus–mediated Brn3b protein expression may be a suitable approach for promoting neuroprotection in animal models of glaucoma. PMID:25587060

Experimental and computational models of neurite extension at a choice point in response to controlled diffusive gradients

NASA Astrophysics Data System (ADS)

Catig, G. C.; Figueroa, S.; Moore, M. J.

2015-08-01

Ojective. Axons are guided toward desired targets through a series of choice points that they navigate by sensing cues in the cellular environment. A better understanding of how microenvironmental factors influence neurite growth during development can inform strategies to address nerve injury. Therefore, there is a need for biomimetic models to systematically investigate the influence of guidance cues at such choice points. Approach. We ran an adapted in silico biased turning axon growth model under the influence of nerve growth factor (NGF) and compared the results to corresponding in vitro experiments. We examined if growth simulations were predictive of neurite population behavior at a choice point. We used a biphasic micropatterned hydrogel system consisting of an outer cell restrictive mold that enclosed a bifurcated cell permissive region and placed a well near a bifurcating end to allow proteins to diffuse and form a gradient. Experimental diffusion profiles in these constructs were used to validate a diffusion computational model that utilized experimentally measured diffusion coefficients in hydrogels. The computational diffusion model was then used to establish defined soluble gradients within the permissive region of the hydrogels and maintain the profiles in physiological ranges for an extended period of time. Computational diffusion profiles informed the neurite growth model, which was compared with neurite growth experiments in the bifurcating hydrogel constructs. Main results. Results indicated that when applied to the constrained choice point geometry, the biased turning model predicted experimental behavior closely. Results for both simulated and in vitro neurite growth studies showed a significant chemoattractive response toward the bifurcated end containing an NGF gradient compared to the control, though some neurites were found in the end with no NGF gradient. Significance. The integrated model of neurite growth we describe will allow comparison of experimental studies against growth cone guidance computational models applied to axon pathfinding at choice points.

Growth cones are actively influenced by substrate-bound adhesion molecules.

PubMed

Burden-Gulley, S M; Payne, H R; Lemmon, V

1995-06-01

As axons advance to appropriate target tissues during development, their growth cones encounter a variety of cell adhesion molecules (CAMs) and extracellular matrix molecules (ECM molecules). Purified CAMs and ECM molecules influence neurite outgrowth in vitro and are thought to have a similar function in vivo. For example, when retinal ganglion cell (RGC) neurons are grown on different CAM and ECM molecule substrates in vitro, their growth cones display distinctive morphologies (Payne et al., 1992). Similarly, RGC growth cones in vivo have distinctive shapes at different points in the pathway from the eye to the tectum, suggesting the presence of localized cues that determine growth cone behaviors such as pathway selection at choice points. In this report, time-lapse video microscopy was utilized to examine dynamic transformations of RGC growth cones as they progressed from L1/8D9, N-cadherin, or laminin onto a different substrate. Contact made by the leading edge of a growth cone with a new substrate resulted in a rapid and dramatic alteration in growth cone morphology. In some cases, the changes encompassed the entire growth cone including those regions not in direct contact with the new substrate. In addition, the growth cones displayed a variety of behavioral responses that were dependent upon the order of substrate contact. These studies demonstrate that growth cones are actively affected by the substrate, and suggest that abrupt changes in the molecular composition of the growth cone environment are influential during axonal pathfinding.

Neuron-specific knockdown of the Drosophila fat induces reduction of life span, deficient locomotive ability, shortening of motoneuron terminal branches and defects in axonal targeting.

PubMed

Nakamura, Aya; Tanaka, Ryo; Morishita, Kazushige; Yoshida, Hideki; Higuchi, Yujiro; Takashima, Hiroshi; Yamaguchi, Masamitsu

2017-07-01

Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system. Neuron-specific knockdown of fat shortened the life span and induced the defect in locomotive abilities of adult flies. In consistent with these phenotypes, defects in synapse structure at neuromuscular junction were observed in neuron-specific fat-knockdown flies. In addition, aberrations in axonal targeting of photoreceptor neuron in third-instar larvae were also observed, suggesting that fat involves in axonal targeting. Taken together, the results indicate that Drosophila fat plays an essential role in formation and/or maintenance of neuron. Both VMS and HS show mental retardation and neuronal defects. We therefore consider that these two rare human diseases could possibly be caused by the defect in FAT4 function in neuronal cells. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

PubMed Central

Bosco, Daryl A.; Morfini, Gerardo; Karabacak, N. Murat; Song, Yuyu; Gros-Louis, Francois; Pasinelli, Piera; Goolsby, Holly; Fontaine, Benjamin A.; Lemay, Nathan; McKenna-Yasek, Diane; Frosch, Matthew P.; Agar, Jeffery N.; Julien, Jean-Pierre; Brady, Scott T.; Brown, Robert H.

2010-01-01

Many mutations confer upon copper/zinc superoxide dismutase-1 (SOD1) one or more toxic function(s) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we demonstrate that oxidized WT-SOD1 and mutant-SOD1 share a conformational epitope that is not present in normal WT-SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord displayed striking C4F6 immunoreactivity, denoting the presence of aberrant WT-SOD1 species. Recombinant, oxidized WT-SOD1 and WT-SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to FALS-linked mutant SOD1. Studies here suggest that WT-SOD1 can be pathogenic in SALS and identifies an SOD1-dependent pathogenic mechanism common to FALS and SALS. PMID:20953194

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

PubMed

Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

2014-02-27

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

The Amniote Oculomotor Complex.

PubMed

Company, Verónica; Moreno-Bravo, Juan Antonio; Perez-Balaguer, Ariadna; Puelles, Eduardo

2018-04-16

The oculomotor (OM) complex is a combination of somatic and parasympatethic neurons. The correct development and wiring of this cranial pair is essential to perform basic functions: eyeball and eyelid movements, pupillary constriction, and lens accommodation. The improper formation or function of this nucleus leads pathologies such as strabismus. We describe the OM organization and function in different vertebrate brains, including chick, mouse, and human. The morphological localization is detailed, as well as the spatial relation with the trochlear nucleus in order to adjust some misleading anatomical topographic descriptions. We detailed the signaling processes needed for the specification of the OM neurons. The transcriptional programs driven the specification and differentiation of these neurons are partially determined. We summarized recent genetic studies that have led to the identification of guidance mechanisms involved in the migration, axon pathfinding, and targeting of the OM neurons. Finally, we overviewed the pathology associated to genetic malformations in the OM development and related clinical alterations. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

The mouse F3/contactin glycoprotein

PubMed Central

Bizzoca, Antonella; Corsi, Patrizia

2009-01-01

F3/Contactin is an immunoglobulin superfamily component expressed in the nervous tissue of several species. Here we focus on the structural and functional properties of its mouse relative, on the mechanisms driving its regulated expression and on its developmental role. F3/Contactin is differentially expressed in distinct populations of central and peripheral neurons and in some non-neuronal cells. Accordingly, the regulatory region of the underlying gene includes promoter elements undergoing differential activation, associated with an intricate splicing profile, indicating that transcriptional and posttranscriptional mechanisms contribute to its expression. Transgenic models allowed to follow F3/Contactin promoter activation in vivo and to modify F3/Contactin gene expression under a heterologous promoter, which resulted in morphological and functional phenotypes. Besides axonal growth and pathfinding, these concerned earlier events, including precursor proliferation and commitment. This wide role in neural ontogenesis is consistent with the recognized interaction of F3/Contactin with developmental control genes belonging to the Notch pathway. PMID:19372728

Genetic interaction of Neuroglian and Semaphorin1a during guidance and synapse formation.

PubMed

Godenschwege, Tanja A; Murphey, Rodney K

2009-01-01

We have previously demonstrated a function for Neuroglian and Semaphorin1a in Drosophila giant fiber circuit formation. Both molecules are required for guiding the giant fibers out of the brain and have distinct functions during giant synapse formation. In this study we characterized the effects of various combinations of Neuroglian and Semaphorin1a gain and loss of function backgrounds on giant fiber circuitry formation. We found that Neuroglian and Semaphorin1a genetically interact with each other during axon guidance as well as during synapse formation. Our experiments revealed that during pathfinding of the giant fibers out of the brain, Neuroglian function seems to be dependent on Semaphorin1a. In contrast, during giant fiber synapse formation we observed that Semaphorin1a signaling as a receptor can be altered by Neuroglian in the same cell. In summary, our findings suggest that Neuroglian and Semaphorin1a can regulate each other's function in cis and that the resultant signaling output is possibly different during guidance and synapse formation.

Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype.

PubMed

Hogan, Alison L; Don, Emily K; Rayner, Stephanie L; Lee, Albert; Laird, Angela S; Watchon, Maxinne; Winnick, Claire; Tarr, Ingrid S; Morsch, Marco; Fifita, Jennifer A; Gwee, Serene S L; Formella, Isabel; Hortle, Elinor; Yuan, Kristy C; Molloy, Mark P; Williams, Kelly L; Nicholson, Garth A; Chung, Roger S; Blair, Ian P; Cole, Nicholas J

2017-07-15

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the death of upper and lower motor neurons. Approximately 10% of cases have a known family history of ALS and disease-linked mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible disease mechanisms, we developed in vitro and in vivo models based on an ALS-linked missense mutation in CCNF. Proteomic analysis of the in vitro models identified the disruption of several cellular pathways in the mutant model, including caspase-3 mediated cell death. Transient overexpression of human CCNF in zebrafish embryos supported this finding, with fish expressing the mutant protein found to have increased levels of cleaved (activated) caspase-3 and increased cell death in the spinal cord. The mutant CCNF fish also developed a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. Importantly, we demonstrated a significant correlation between the severity of the CCNF-induced axonopathy and a reduced motor response to a light stimulus (photomotor response). This is the first report of an ALS-linked CCNF mutation in vivo and taken together with the in vitro model identifies the disruption of cell death pathways as a significant consequence of this mutation. Additionally, this study presents a valuable new tool for use in ongoing studies investigating the pathobiology of ALS-linked CCNF mutations. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting.

PubMed

Dung, Vuu My; Suong, Dang Ngoc Anh; Okamaoto, Yuji; Hiramatsu, Yu; Thao, Dang Thi Phuong; Yoshida, Hideki; Takashima, Hiroshi; Yamaguchi, Masamitsu

2018-05-15

Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan-neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy. Copyright © 2018 Elsevier Inc. All rights reserved.

Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex

PubMed Central

Xing, Lei; Larsen, Rylan S; Bjorklund, George Reed; Li, Xiaoyan; Wu, Yaohong; Philpot, Benjamin D; Snider, William D; Newbern, Jason M

2016-01-01

Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2+ neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability. DOI: http://dx.doi.org/10.7554/eLife.11123.001 PMID:26848828

Sensory cortex limits cortical maps and drives top-down plasticity in thalamocortical circuits

PubMed Central

Zembrzycki, Andreas; Chou, Shen-Ju; Ashery-Padan, Ruth; Stoykova, Anastassia; O’Leary, Dennis D.M.

2013-01-01

Summary Primary somatosensory cortex (S1) contains a complete body map that mirrors subcortical maps developed by peripheral sensory input projecting to sensory hindbrain, thalamus, then S1. Peripheral changes during development alter these maps through ‘bottom-up’ plasticity. Unknown is how S1 size influences map organization and if an altered S1 map feedbacks to affect subcortical maps. We show in mice that S1 is significantly reduced by cortex-specific deletion of Pax6, resulting in a reduced body map and loss of body representations by exclusion of later-differentiating sensory thalamocortical input. An initially normal sensory thalamus was re-patterned to match the aberrant S1 map by apoptotic deletion of thalamic neurons representing body parts with axons excluded from S1. Deleted representations were rescued by altering competition between thalamocortical axons by sensory deprivation or increasing S1. Thus, S1 size determined resolution and completeness of body maps and engaged ‘top-down’ plasticity that re-patterned sensory thalamus to match S1. PMID:23831966

Dynamic Pathfinders: Leveraging Your OPAC to Create Resource Guides

ERIC Educational Resources Information Center

Hunter, Ben

2008-01-01

Library pathfinders are a time-tested method of leading library users to important resources. However, paper-based pathfinders suffer from space limitations, and both paper-based and Web-based pathfinders require frequent updates to keep up with new library acquisitions. This article details a step-by-step method to create an online dynamic…

Pathfinder aircraft taking off - setting new solar powered altitude record

NASA Technical Reports Server (NTRS)

1995-01-01

The Pathfinder solar-powered remotely piloted aircraft climbs to a record-setting altitude of 50,567 feet during a flight Sept. 11, 1995, at NASA's Dryden Flight Research Center, Edwards, California. Pathfinder was a lightweight, solar-powered, remotely piloted flying wing aircraft used to demonstrate the use of solar power for long-duration, high-altitude flight. Its name denotes its mission as the 'Pathfinder' or first in a series of solar-powered aircraft that will be able to remain airborne for weeks or months on scientific sampling and imaging missions. Solar arrays covered most of the upper wing surface of the Pathfinder aircraft. These arrays provided up to 8,000 watts of power at high noon on a clear summer day. That power fed the aircraft's six electric motors as well as its avionics, communications, and other electrical systems. Pathfinder also had a backup battery system that could provide power for two to five hours, allowing for limited-duration flight after dark. Pathfinder flew at airspeeds of only 15 to 20 mph. Pitch control was maintained by using tiny elevators on the trailing edge of the wing while turns and yaw control were accomplished by slowing down or speeding up the motors on the outboard sections of the wing. On September 11, 1995, Pathfinder set a new altitude record for solar-powered aircraft of 50,567 feet above Edwards Air Force Base, California, on a 12-hour flight. On July 7, 1997, it set another, unofficial record of 71,500 feet at the Pacific Missile Range Facility, Kauai, Hawaii. In 1998, Pathfinder was modified into the longer-winged Pathfinder Plus configuration. (See the Pathfinder Plus photos and project description.)

Imaging of Cranial Nerves III, IV, VI in Congenital Cranial Dysinnervation Disorders

PubMed Central

Kim, Jae Hyoung

2017-01-01

Congenital cranial dysinnervation disorders are a group of diseases caused by abnormal development of cranial nerve nuclei or their axonal connections, resulting in aberrant innervation of the ocular and facial musculature. Its diagnosis could be facilitated by the development of high resolution thin-section magnetic resonance imaging. The purpose of this review is to describe the method to visualize cranial nerves III, IV, and VI and to present the imaging findings of congenital cranial dysinnervation disorders including congenital oculomotor nerve palsy, congenital trochlear nerve palsy, Duane retraction syndrome, Möbius syndrome, congenital fibrosis of the extraocular muscles, synergistic divergence, and synergistic convergence. PMID:28534340

The Original Social Network: White Matter and Social Cognition.

PubMed

Wang, Yin; Olson, Ingrid R

2018-06-01

Social neuroscience has traditionally focused on the functionality of gray matter regions, ignoring the critical role played by axonal fiber pathways in supporting complex social processes. In this paper, we argue that research on white matter is essential for understanding a range of topics in social neuroscience, such as face processing, theory of mind, empathy, and imitation, as well as clinical disorders defined by aberrant social behavior, such as prosopagnosia, autism, and schizophrenia. We provide practical advice on how best to carry out these studies, which ultimately will substantially deepen our understanding of the neurobiological basis of social behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pathfinder aircraft taking off - setting new solar powered altitude record

NASA Technical Reports Server (NTRS)

1995-01-01

The Pathfinder solar-powered remotely piloted aircraft climbs to a record-setting altitude of 50,567 feet during a flight Sept. 11, 1995, at NASA's Dryden Flight Research Center, Edwards, California. The flight was part of the NASA ERAST (Environmental Research Aircraft and Sensor Technology) program. The Pathfinder was designed and built by AeroVironment Inc., Monrovia, California. Solar arrays cover nearly all of the upper wing surface and produce electricity to power the aircraft's six motors. Pathfinder was a lightweight, solar-powered, remotely piloted flying wing aircraft used to demonstrate the use of solar power for long-duration, high-altitude flight. Its name denotes its mission as the 'Pathfinder' or first in a series of solar-powered aircraft that will be able to remain airborne for weeks or months on scientific sampling and imaging missions. Solar arrays covered most of the upper wing surface of the Pathfinder aircraft. These arrays provided up to 8,000 watts of power at high noon on a clear summer day. That power fed the aircraft's six electric motors as well as its avionics, communications, and other electrical systems. Pathfinder also had a backup battery system that could provide power for two to five hours, allowing for limited-duration flight after dark. Pathfinder flew at airspeeds of only 15 to 20 mph. Pitch control was maintained by using tiny elevators on the trailing edge of the wing while turns and yaw control were accomplished by slowing down or speeding up the motors on the outboard sections of the wing. On September 11, 1995, Pathfinder set a new altitude record for solar-powered aircraft of 50,567 feet above Edwards Air Force Base, California, on a 12-hour flight. On July 7, 1997, it set another, unofficial record of 71,500 feet at the Pacific Missile Range Facility, Kauai, Hawaii. In 1998, Pathfinder was modified into the longer-winged Pathfinder Plus configuration. (See the Pathfinder Plus photos and project description.)

Teaching, Learning, and Planetary Exploration

NASA Technical Reports Server (NTRS)

Brown, Robert A.

2002-01-01

This is the final report of a program that examined the fundamentals of education associated with space activities, promoted educational policy development in appropriate forums, and developed pathfinder products and services to demonstrate the utility of advanced communication technologies for space-based education. Our focus was on space astrophysics and planetary exploration, with a special emphasis on the themes of the Origins Program, with which the Principal Investigator (PI) had been involved from the outset. Teaching, Learning, and Planetary Exploration was also the core funding of the Space Telescope Science Institute's (ST ScI) Special Studies Office (SSO), and as such had provided basic support for such important NASA studies as the fix for Hubble Space Telescope (HST) spherical aberration, scientific conception of the HST Advanced Camera, specification of the Next-Generation Space Telescope (NGST), and the strategic plan for the second decade of the HST science program.

MARS PATHFINDER CAMERA TEST IN SAEF-2

NASA Technical Reports Server (NTRS)

1996-01-01

In the Spacecraft Assembly and Encapsulation Facility-2 (SAEF-2), workers from the Jet Propulsion Laboratory (JPL) are conducting a systems test of the imager for the Mars Pathfinder. Mounted on the Pathfinder lander, the imager (the white cylindrical element the worker is touching) is a specially designed camera featuring a stereo-imaging system with color capability provided by a set of selectable filters. It is mounted on an extendable mast that will pop up after the lander touches down on the Martian surface. The imager will transmit images of the terrain, allowing engineers back on Earth to survey the landing site before the Pathfinder rover is deployed to explore the area. The Mars Pathfinder is scheduled for launch aboard a Delta II expendable launch vehicle on Dec. 2. JPL manages the Pathfinder project for NASA.

Mars Pathfinder Status at Launch

NASA Technical Reports Server (NTRS)

Spear, A. J.; Freeman, Delma C., Jr.; Braun, Robert D.

1996-01-01

The Mars Pathfinder Flight System is in final test, assembly and launch preparations at the Kennedy Space Center in Florida. Launch is scheduled for 2 Dec. 1996. The Flight System development, in particular the Entry, Descent, and Landing (EDL) system, was a major team effort involving JPL, other NASA centers and industry. This paper provides a summary Mars Pathfinder description and status at launch. In addition, a section by NASA's Langley Research Center, a key EDL contributor, is provided on their support to Mars Pathfinder. This section is included as an example of the work performed by Pathfinder team members outside JPL.

Pathfinder aircraft liftoff on altitude record setting flight of 71,500 feet

NASA Technical Reports Server (NTRS)

1997-01-01

The Pathfinder aircraft has set a new unofficial world record for high-altitude flight of over 71,500 feet for solar-powered aircraft at the U.S. Navy's Pacific Missile Range Facility, Kauai, Hawaii. Pathfinder was designed and manufactured by AeroVironment, Inc, of Simi Valley, California, and was operated by the firm under a jointly sponsored research agreement with NASA's Dryden Flight Research Center, Edwards, California. Pathfinder's record-breaking flight occurred July 7, 1997. The aircraft took off at 11:34 a.m. PDT, passed its previous record altitude of 67,350 feet at about 5:45 p.m. and then reached its new record altitude at 7 p.m. The mission ended with a perfect nighttime landing at 2:05 a.m. PDT July 8. The new record is the highest altitude ever attained by a propellor-driven aircraft. Before Pathfinder, the altitude record for propellor-driven aircraft was 67,028 feet, set by the experimental Boeing Condor remotely piloted aircraft. Pathfinder was a lightweight, solar-powered, remotely piloted flying wing aircraft used to demonstrate the use of solar power for long-duration, high-altitude flight. Its name denotes its mission as the 'Pathfinder' or first in a series of solar-powered aircraft that will be able to remain airborne for weeks or months on scientific sampling and imaging missions. Solar arrays covered most of the upper wing surface of the Pathfinder aircraft. These arrays provided up to 8,000 watts of power at high noon on a clear summer day. That power fed the aircraft's six electric motors as well as its avionics, communications, and other electrical systems. Pathfinder also had a backup battery system that could provide power for two to five hours, allowing for limited-duration flight after dark. Pathfinder flew at airspeeds of only 15 to 20 mph. Pitch control was maintained by using tiny elevators on the trailing edge of the wing while turns and yaw control were accomplished by slowing down or speeding up the motors on the outboard sections of the wing. On September 11, 1995, Pathfinder set a new altitude record for solar-powered aircraft of 50,567 feet above Edwards Air Force Base, California, on a 12-hour flight. On July 7, 1997, it set another, unofficial record of 71,500 feet at the Pacific Missile Range Facility, Kauai, Hawaii. In 1998, Pathfinder was modified into the longer-winged Pathfinder Plus configuration. (See the Pathfinder Plus photos and project description.)

Pathfinder landing sites at candidate SNC impact ejection sites

NASA Technical Reports Server (NTRS)

Golombek, Matthew P.

1994-01-01

If Mars Pathfinder were able to land at a site on Mars from which the SNC meteorites were ejected by impact, the Pathfinder mission would essentially represent a very inexpensive sample return mission. Geologic units that contain four potential impact craters from which SNC meteorites could have been ejected from Mars are accessible to the Mars Pathfinder lander. Determining that SNC meteorites came from a particular spot on Mars raises the intriguing possibility of using Pathfinder as a sample return mission and providing a radiometric age for the considerably uncertain martian crater-age timescale. Pathfinder instruments are capable of determining if the rock type at the landing site is similar to that of one or more of the SNC meteorites, which would strengthen the hypothesis that the SNC meteorites did, in fact, come from Mars. Unfortunately, instrument observations from Pathfinder are probably not capable of determining if the geologic unit sampled by the lander is definitively the unit from which a SNC meteorite came from as opposed to Mars in general or perhaps a particular region on Mars. This abstract evaluates the possibility of landing at potential SNC ejection sites and the ability of Pathfinder to identify the landing site as the place from which an SNC meteorite came.

A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease.

PubMed

Clark, Jayden A; Yeaman, Elise J; Blizzard, Catherine A; Chuckowree, Jyoti A; Dickson, Tracey C

2016-01-01

Amyotrophic lateral sclerosis (ALS) is an aggressive multifactorial disease converging on a common pathology: the degeneration of motor neurons (MNs), their axons and neuromuscular synapses. This vulnerability and dysfunction of MNs highlights the dependency of these large cells on their intracellular machinery. Neuronal microtubules (MTs) are intracellular structures that facilitate a myriad of vital neuronal functions, including activity dependent axonal transport. In ALS, it is becoming increasingly apparent that MTs are likely to be a critical component of this disease. Not only are disruptions in this intracellular machinery present in the vast majority of seemingly sporadic cases, recent research has revealed that mutation to a microtubule protein, the tubulin isoform TUBA4A, is sufficient to cause a familial, albeit rare, form of disease. In both sporadic and familial disease, studies have provided evidence that microtubule mediated deficits in axonal transport are the tipping point for MN survivability. Axonal transport deficits would lead to abnormal mitochondrial recycling, decreased vesicle and mRNA transport and limited signaling of key survival factors from the neurons peripheral synapses, causing the characteristic peripheral "die back". This disruption to microtubule dependant transport in ALS has been shown to result from alterations in the phenomenon of microtubule dynamic instability: the rapid growth and shrinkage of microtubule polymers. This is accomplished primarily due to aberrant alterations to microtubule associated proteins (MAPs) that regulate microtubule stability. Indeed, the current literature would argue that microtubule stability, particularly alterations in their dynamics, may be the initial driving force behind many familial and sporadic insults in ALS. Pharmacological stabilization of the microtubule network offers an attractive therapeutic strategy in ALS; indeed it has shown promise in many neurological disorders, ALS included. However, the pathophysiological involvement of MTs and their functions is still poorly understood in ALS. Future investigations will hopefully uncover further therapeutic targets that may aid in combating this awful disease.

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

PubMed Central

Tsai, Shang-Yi A.; Pokrass, Michael J.; Klauer, Neal R.; Nohara, Hiroshi; Su, Tsung-Ping

2015-01-01

Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor’s interaction with myristic acid. In Sig-1R–KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R–KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R–KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25. PMID:25964330

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.

PubMed

Tsai, Shang-Yi A; Pokrass, Michael J; Klauer, Neal R; Nohara, Hiroshi; Su, Tsung-Ping

2015-05-26

Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.

Pathfinder ground preparations prior to altitude record setting flight of 71,500 feet

NASA Technical Reports Server (NTRS)

1997-01-01

Technicians make final adjustments on the solar-powered Pathfinder remotely piloted research aircraft prior to the craft's taking off on a flight which established a new unofficial world's altitude record for both propellor-driven and solar-powered aircraft. The new record of more than 71,500 feet was set during a 14 1/2-hour flight July 7, 1997, from the U.S. Navy's Pacific Missile Range Facility (PMRF) at Barking Sands, Kauai, Hawaii. The new altitude record is subject to verification by the National Aeronautics Association. The Pathfinder took off at 8:34 a.m. HDT, passed its previous record altitude of 67,350 feet about 2:45 p.m., and then reached its new mark at about 4 p.m. Controllers on the ground then initiated a slow decent, and Pathfinder landed seven hours later at 11:05 p.m. HDT. The experimental Boeing Condor remotely-piloted aircraft had held the previous record for propellor-driven craft of 67,028 feet. The Pathfinder had exceeded that height on a previous flight on June 9, 1997, but not by a large enough margin to be considered a new record. Pathfinder was a lightweight, solar-powered, remotely piloted flying wing aircraft used to demonstrate the use of solar power for long-duration, high-altitude flight. Its name denotes its mission as the 'Pathfinder' or first in a series of solar-powered aircraft that will be able to remain airborne for weeks or months on scientific sampling and imaging missions. Solar arrays covered most of the upper wing surface of the Pathfinder aircraft. These arrays provided up to 8,000 watts of power at high noon on a clear summer day. That power fed the aircraft's six electric motors as well as its avionics, communications, and other electrical systems. Pathfinder also had a backup battery system that could provide power for two to five hours, allowing for limited-duration flight after dark. Pathfinder flew at airspeeds of only 15 to 20 mph. Pitch control was maintained by using tiny elevators on the trailing edge of the wing while turns and yaw control were accomplished by slowing down or speeding up the motors on the outboard sections of the wing. On September 11, 1995, Pathfinder set a new altitude record for solar-powered aircraft of 50,567 feet above Edwards Air Force Base, California, on a 12-hour flight. On July 7, 1997, it set another, unofficial record of 71,500 feet at the Pacific Missile Range Facility, Kauai, Hawaii. In 1998, Pathfinder was modified into the longer-winged Pathfinder Plus configuration. (See the Pathfinder Plus photos and project description.)

Imaging of Cranial Nerves III, IV, VI in Congenital Cranial Dysinnervation Disorders.

PubMed

Kim, Jae Hyoung; Hwang, Jeong Min

2017-06-01

Congenital cranial dysinnervation disorders are a group of diseases caused by abnormal development of cranial nerve nuclei or their axonal connections, resulting in aberrant innervation of the ocular and facial musculature. Its diagnosis could be facilitated by the development of high resolution thin-section magnetic resonance imaging. The purpose of this review is to describe the method to visualize cranial nerves III, IV, and VI and to present the imaging findings of congenital cranial dysinnervation disorders including congenital oculomotor nerve palsy, congenital trochlear nerve palsy, Duane retraction syndrome, Möbius syndrome, congenital fibrosis of the extraocular muscles, synergistic divergence, and synergistic convergence. © 2017 The Korean Ophthalmological Society.

Genetic Interaction of Neuroglian and Semaphorin1a during Guidance and Synapse Formation

PubMed Central

Godenschwege, Tanja A.; Murphey, Rodney K.

2009-01-01

We have previously demonstrated a function for Neuroglian and Semaphorin1a in Drosophila giant fiber circuit formation. Both molecules are required for guiding the giant fibers out of the brain and have distinct functions during giant synapse formation. In this study we characterized the effects of various combinations of Neuroglian and Semaphorin1a gain and loss of function backgrounds on giant fiber circuitry formation. We found that Neuroglian and Semaphorin1a genetically interact with each other during axon guidance as well as during synapse formation. Our experiments revealed that during pathfinding of the giant fibers out of the brain, Neuroglian function seems to be dependent on Semaphorin1a. In contrast, during giant fiber synapse formation we observed that Semaphorin1a signaling as a receptor can be altered by Neuroglian in the same cell. In summary, our findings suggest that Neuroglian and Semaphorin1a can regulate each other’s function in cis and that the resultant signaling output is possibly different during guidance and synapse formation. PMID:19052954

The semantic pathfinder: using an authoring metaphor for generic multimedia indexing.

PubMed

Snoek, Cees G M; Worring, Marcel; Geusebroek, Jan-Mark; Koelma, Dennis C; Seinstra, Frank J; Smeulders, Arnold W M

2006-10-01

This paper presents the semantic pathfinder architecture for generic indexing of multimedia archives. The semantic pathfinder extracts semantic concepts from video by exploring different paths through three consecutive analysis steps, which we derive from the observation that produced video is the result of an authoring-driven process. We exploit this authoring metaphor for machine-driven understanding. The pathfinder starts with the content analysis step. In this analysis step, we follow a data-driven approach of indexing semantics. The style analysis step is the second analysis step. Here, we tackle the indexing problem by viewing a video from the perspective of production. Finally, in the context analysis step, we view semantics in context. The virtue of the semantic pathfinder is its ability to learn the best path of analysis steps on a per-concept basis. To show the generality of this novel indexing approach, we develop detectors for a lexicon of 32 concepts and we evaluate the semantic pathfinder against the 2004 NIST TRECVID video retrieval benchmark, using a news archive of 64 hours. Top ranking performance in the semantic concept detection task indicates the merit of the semantic pathfinder for generic indexing of multimedia archives.

A Post-Pathfinder Evaluation of Areocentric Solar Coordinates with Improved Timing Recipes for Mars Seasonal/Diurnal Climate Studies

NASA Technical Reports Server (NTRS)

Allison, Michael; McEwen, Megan

1999-01-01

The accurate determination of the Mars pole vector derived from Pathfinder and Viking Lander radio data, together with the VSOP87 representation of planetary orbits, have been applied to a new evaluation of the right ascension of the "fictitious mean sun" (FMS) at Mars. With DELTA t (sub J2000) the elapsed time in days from the J2000 epoch (J.D.2451545.0 (sup TT), alpha FMS = 270 degrees.3863 + 0.52403840(degrees/d) (raised dot) DELTA T (sub j2000) - 4 x 10 (exp -13) (degrees/d (sup 2)) (raised dot) DELTA t (sup 2) (sub J2000) represents a best least-squares quadratic fit of the FMS, including aberration, to each instance of the four equinox and solstice passages for each of 134 Mars orbits spanning the calendar years 1874-2127. The implied tropical orbit period for Mars, 686.9726 (sup d), closely agrees with the recent evaluations. Together with the Pathfinder radio determination of the Mars sidereal rotation, the derived FMS rate corresponds to a mean solar day (or "sol") of 1.027491251 (sup d). The new FMS determination would serve to define the Mean Solar Time at Mars to the nearest tenth-second, according to historical conventions originally established for terrestrial time keeping, once the Mars prime meridian defined by the crater Airy-O is navigated to the same accuracy. For convenient reference to current epochs, 2000 Jan 06 00:00 UTC (= MJD 51549.000 (sup UTC)) corresponds to a coincidence of (alpha (sub FMS)) and the rotation angle of the crater Airy-O measured with respect to the Mars equinox (i.e. "mean solar midnight" on the planet's prime meridian), to within the current uncertainty of several seconds in the locational definition of the planet's cartographic grid. As a further result of the analysis, the consistently derived Mars obliquity of date is epsilon = 25 degrees.192 + 3.45 x l0 (exp -7)(degrees/d)(raised dot) DELTA t (sub J2000). An improved analytic recipe for the calculation of the solar areocentric longitude (L (sub s)) of Mars to an accuracy of 0 degrees.01 is also provided, accounting for the primary perturbations of Earth, Jupiter, and Venus, which may in turn be applied to an efficient evaluation of Mars local true solar time (LTST) to within the uncertainty of the inertial position of the Mars prime meridian. For specific applications to the data archives for landed Mars spacecraft, simple conversion formulae are given for the determination of the Viking "Local Lander Time" and the Pathfinder "Local True Solar Time" in terms of the terrestrial calendar date and UTC.

Navigation Flight Operations for Mars Pathfinder

NASA Technical Reports Server (NTRS)

Vaughan, Robin M.; Kallemeyn, Pieter H., Jr.; Spencer, David A.; Braun, Robert D.

2004-01-01

On July 4, 1997, Mars Pathfinder became the first spacecraft to land on the surface of Mars in 21 years. Pathfinder was launched on December 4, 1996 and spent seven months en route to the red planet. This report discusses the navigation flight experience for the Mars Pathfinder interplanetary cruise. In particular, orbit determination and maneuver design and execution results are presented. Special emphasis is given to the navigation role in the days and hours leading up to and including the Entry, Descent, and Landing (EDL) phase.

Validating the Usefulness of Combined Japanese GMS Data For Long-Term Global Change Studies

NASA Technical Reports Server (NTRS)

Simpson, James J.; Dodge, James C. (Technical Monitor)

2001-01-01

The primary objectives of the Geostationary Meteorological Satellite (GMS)-5 Pathfinder Project were the following: (1) to evaluate GMS-5 data for sources of error and develop methods for minimizing any such errors in GMS-5 data; (2) to prepare a GMS-5 Pathfinder data set for the GMS-5 Pathfinder Benchmark Period (1 July 95 - 30 June 96); and (3) show the usefulness of the improved Pathfinder data set in at least one geophysical application. All objectives were met.

Testing of the LISA pathfinder GRS

NASA Astrophysics Data System (ADS)

Antonucci, Federica; Cavalleri, Antonella; Ciani, Giacomo; Congedo, Giuseppe; Dolesi, Rita; de Marchi, Fabrizio; Ferraioli, Luigi; Hueller, Mauro; Nicolodi, Daniele; Tombolato, David; Vitale, Stefano; Wass, Peter J.; Weber, William J.

The ESA/NASA mission,LISA (Laser Interferometric Space Antenna), will measure gravita-tional waves emitted by astronomical sources, galactic and extra-galactic, at frequencies 10-4 to 10-1 Hz. LISA is a 5-million-km arm-length interferometer whose mirrors are test masses which must be nominally free-falling to a level which does not exceed 3 · 10-15 ms-2 Hz -1/2 in acceleration. LISA Pathfinder is a technology demonstration mission which will show that the relative parasitic acceleration between two masses on one spacecraft can be lower than 3 · 10-14 ms-2 Hz -1/2 , at frequencies around 1 mHz -one order of magnitude larger than LISA's goal. At the core of the LISA Pathfinder experiment is the GRS (gravitational reference sensor), a capacitive sensor with mm gaps used to measure the position of the test mass and actuate its position in 6-degrees-of-freedom. Testing the purity of free-fall for LISA Pathfinder on-ground is achieved using a torsion pendulum which allows us to measure force disturbances at a level relevant to LISA Pathfinder. We will present the latest campaign of tests of the LISA Pathfinder GRS using the 4-test-mass torsion pendulum facility aimed at measuring force-noise sources (responsible for the parasitic acceleration) for LISA Pathfinder in its frequency band. Our GRS , is the LISA Pathfinder flight-model replica, and its testing is crucial in verifying the design and performance of the flight instrument and measuring many of the unwanted disturbances which can limit the performance of LISA and LISA pathfinder. The measurements concern the dependence of the force on the test mass position in the sensor and their electrostatic coupling, electrostatic fields due to surface-potential variations and thermal gradients.

Airbag retraction

NASA Technical Reports Server (NTRS)

1997-01-01

This image shows that the Mars Pathfinder airbags have been successfully retracted, allowing safe deployment of the rover ramps. The Sojourner rover is at lower right, and rocks are visible in the background. Mars Pathfinder landed successfully on the surface of Mars today at 10:07 a.m. PDT.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Space Science

NASA Image and Video Library

1996-12-04

The Mars Pathfinder began the journey to Mars with liftoff atop a Delta II expendable launch vehicle from launch Complex 17B on Cape Canaveral Air Station. The Mars Pathfinder traveled on a direct trajectory to Mars, and arrived there in July 1997. Mars Pathfinder sent a lander and small robotic rover, Sojourner, to the surface of Mars. The primary objective of the mission was to demonstrate a low-cost way of delivering a science package to the surface of Mars using a direct entry, descent and landing with the aid of small rocket engines, a parachute, airbags and other techniques. In addition, landers and rovers of the future will share the heritage of Mars Pathfinder designs and technologies first tested in this mission. Pathfinder also collected invaluable data about the Martian surface.

Identification of metabolic pathways using pathfinding approaches: a systematic review.

PubMed

Abd Algfoor, Zeyad; Shahrizal Sunar, Mohd; Abdullah, Afnizanfaizal; Kolivand, Hoshang

2017-03-01

Metabolic pathways have become increasingly available for various microorganisms. Such pathways have spurred the development of a wide array of computational tools, in particular, mathematical pathfinding approaches. This article can facilitate the understanding of computational analysis of metabolic pathways in genomics. Moreover, stoichiometric and pathfinding approaches in metabolic pathway analysis are discussed. Three major types of studies are elaborated: stoichiometric identification models, pathway-based graph analysis and pathfinding approaches in cellular metabolism. Furthermore, evaluation of the outcomes of the pathways with mathematical benchmarking metrics is provided. This review would lead to better comprehension of metabolism behaviors in living cells, in terms of computed pathfinding approaches. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Mars Pathfinder Atmospheric Entry Navigation Operations

NASA Technical Reports Server (NTRS)

Braun, R. D.; Spencer, D. A.; Kallemeyn, P. H.; Vaughan, R. M.

1997-01-01

On July 4, 1997, after traveling close to 500 million km, the Pathfinder spacecraft successfully completed entry, descent, and landing, coming to rest on the surface of Mars just 27 km from its target point. In the present paper, the atmospheric entry and approach navigation activities required in support of this mission are discussed. In particular, the flight software parameter update and landing site prediction analyses performed by the Pathfinder operations navigation team are described. A suite of simulation tools developed during Pathfinder's design cycle, but extendible to Pathfinder operations, are also presented. Data regarding the accuracy of the primary parachute deployment algorithm is extracted from the Pathfinder flight data, demonstrating that this algorithm performed as predicted. The increased probability of mission success through the software parameter update process is discussed. This paper also demonstrates the importance of modeling atmospheric flight uncertainties in the estimation of an accurate landing site. With these atmospheric effects included, the final landed ellipse prediction differs from the post-flight determined landing site by less then 0.5 km in downtrack.

Integrating Subject Pathfinders into Online Catalogs.

ERIC Educational Resources Information Center

Jarvis, William E.

1985-01-01

Discusses the integration of subject pathfinders into online public access catalogs (OPAC) through following features: within the OPAC, offline user guide manuals, remotely printed upon user request, or online as saved searches displayed in help screen format. Excerpts of a pathfinder display for biotechnology are presented. Four sources are…

Software Aids Visualization Of Mars Pathfinder Mission

NASA Technical Reports Server (NTRS)

Weidner, Richard J.

1996-01-01

Report describes Simulator for Imager for Mars Pathfinder (SIMP) computer program. SIMP generates "virtual reality" display of view through video camera on Mars lander spacecraft of Mars Pathfinder mission, along with display of pertinent textual and graphical data, for use by scientific investigators in planning sequences of activities for mission.

Pathfinder Rear Ramp

NASA Image and Video Library

1997-07-06

NASA's Mars Pathfinder's rear rover ramp can be seen successfully unfurled in this image, taken at the end of Sol 2 by the Imager for Mars Pathfinder (IMP). This ramp was later used for the deployment of the microrover Sojourner, which occurred at the end of Sol 2. Areas of a lander petal and deflated airbag are visible at left. The image helped Pathfinder scientists determine that the rear ramp was the one to use for rover deployment. At upper right is the rock dubbed "Barnacle Bill," which Sojourner will later study. http://photojournal.jpl.nasa.gov/catalog/PIA00627

JWST Pathfinder Telescope Risk Reduction Cryo Test Program

NASA Technical Reports Server (NTRS)

Matthews, Gary W.; Scorse, Thomas R.; Spina, John A.; Noel, Darin M.; Havey, Keith A., Jr.; Huguet, Jesse A.; Whitman, Tony L.; Wells, Conrad; Walker, Chanda B.; Lunt, Sharon;

Airbag retraction

NASA Technical Reports Server (NTRS)

1997-01-01

This image shows that the Mars Pathfinder airbags have been successfully retracted, allowing safe deployment of the rover ramps. The Sojourner rover, still in its deployed position, is at center image, and rocks are visible in the background. Mars Pathfinder landed successfully on the surface of Mars today at 10:07 a.m. PDT.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

MESUR Pathfinder Science Investigations

NASA Technical Reports Server (NTRS)

Golombek, M.

1993-01-01

The MESUR (Mars Environmental Survey) Pathfinder mission is the first Discovery mission planned for launch in 1996. MESUR Pathfinder is designed as an engineering demonstration of the entry, descent and landing approach to be employed by the follow-on MESUR Network mission, which will land of order 10 small stations on the surface of Mars to investigate interior, atmospheric and surface properties. Pathfinder is a small Mars lander, equipped with a microrover to deploy instruments and explore the local landing site. Instruments selected for Pathfinder include a surface imager on a 1 m pop-up mast (stereo with spectral filters), an atmospheric structure instrument/surface meteorology package, and an alpha proton x-ray spectrometer. The microrover will carry the alpha proton x-ray spectrometer to a number of different rocks and surface materials and provide close-up imaging...

Reduction and Analysis of Meteorology Data from the Mars Pathfinder Lander

NASA Technical Reports Server (NTRS)

Murphy, James R.; Bridger, Alison F. C.; Haberle, Robert M.

1998-01-01

Dr. James Murphy is a member of the Mars Pathfinder Atmospheric Structure Investigation Meteorology (ASI/MET) Science Team. The activities of Dr. Murphy, and his collaborators are summarized in this report, which reviews the activities in support of the analysis of the meteorology data from the Mars Pathfinder Lander.

Martian Surface & Pathfinder Airbags

NASA Technical Reports Server (NTRS)

1997-01-01

This image of the Martian surface was taken in the afternoon of Mars Pathfinder's first day on Mars. Taken by the Imager for Mars Pathfinder (IMP camera), the image shows a diversity of rocks strewn in the foreground. A hill is visible in the distance (the notch within the hill is an image artifact). Airbags are seen at the lower right.

The IMP is a stereo imaging system with color capability provided by 24 selectable filters -- twelve filters per 'eye.' It stands 1.8 meters above the Martian surface, and has a resolution of two millimeters at a range of two meters.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

AVHRR-Based Polar Pathfinder Products: Evaluation, Enhancement, and Transition to MODIS

NASA Technical Reports Server (NTRS)

Fowler, Charles; Maslanik, James; Stone, Robert; Stroeve, Julienne; Emery, William

2001-01-01

The AVHRR-Based Polar Pathfinder (APP) products include calibrated AVHRR channel data, surface temperatures, albedo, satellite scan and solar geometries, and a cloud mask composited into twice- per-day images, and daily averaged fields of sea ice motion, for regions poleward of 50 deg. latitude. Our goals under this grant, in general, are four-fold: 1. To quantify the APP accuracy and sources of error by comparing Pathfinder products with field measurements. 2. To determine the consistency of mean fields and trends in comparison with longer time series of available station data and forecast model output. 3. To investigate the consistency of the products between the different AVHRR instruments over the 1982-present period of the NOAA program. 4. To compare an annual cycle of the AVHRR Pathfinder products with MODIS to establish a baseline for extending Pathfinder-type products into the new ESE period. Year One tasks include intercomparisons of the Pathfinder products with field measurements, testing of algorithm assumptions, collection of field data, and further validation and possible improvement of the multi-sensor ice motion fields. Achievements for these tasks are summarized below.

The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis

PubMed Central

Auletta, Jeffery J; Bartholomew, Amelia M; Maziarz, Richard T; Deans, Robert J; Miller, Robert H; Lazarus, Hillard M; Cohen, Jeffrey A

2012-01-01

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS for which only partially effective therapies exist. Intense research defining the underlying immune pathophysiology is advancing both the understanding of MS as well as revealing potential targets for disease intervention. Mesenchymal stromal cell (MSC) therapy has the potential to modulate aberrant immune responses causing demyelination and axonal injury associated with MS, as well as to repair and restore damaged CNS tissue and cells. This article reviews the pathophysiology underlying MS, as well as providing a cutting-edge perspective into the field of MSC therapy based upon the experience of authors intrinsically involved in MS and MSC basic and translational science research. PMID:22642335

MARS PATHFINDER PYRO SYSTEMS SWITCHING ACTIVITY

NASA Technical Reports Server (NTRS)

1996-01-01

The Mars Pathfinder lander is subjected to a electrical and functional tests of its pyrotechic petal deployer system by Jet Propulsion Laboratory (JPL) engineers and technicians in KSC's Spacecraft Assembly and Encapsulation Facility (SAEF-2). In the background is the Pathfinder cruise stage, which the lander will be mated to once its functional tests are complete. The lander will remain attached to this stage during its six-to-seven-month journey to Mars. When the lander touches down on the surface of Mars next year, the pyrotechnic system will deploy its three petals open like a flower and allow the Sojourner autonomous rover to explore the Martian surface. The Mars Pathfinder is scheduled for launch aboard a Delta II expendable launch vehicle on Dec. 2, the beginning of a 24-day launch period. JPL is managing the Mars Pathfinder project for NASA.

Terrain at Landing Site

NASA Image and Video Library

1997-07-05

Portions of Mars Pathfinder's deflated airbags (seen in the foreground), a large rock in mid-field, and a hill in the background were taken by the Imager for Mars Pathfinder (IMP) aboard Mars Pathfinder during the spacecraft's first day on the Red Planet. Pathfinder successfully landed on Mars at 10:07 a.m. PDT earlier today. The IMP is a stereo imaging system with color capability provided by 24 selectable filters -- twelve filters per "eye." It stands 1.8 meters above the Martian surface, and has a resolution of two millimeters at a range of two meters. http://photojournal.jpl.nasa.gov/catalog/PIA00615

A review of parameters and heuristics for guiding metabolic pathfinding.

PubMed

Kim, Sarah M; Peña, Matthew I; Moll, Mark; Bennett, George N; Kavraki, Lydia E

2017-09-15

Recent developments in metabolic engineering have led to the successful biosynthesis of valuable products, such as the precursor of the antimalarial compound, artemisinin, and opioid precursor, thebaine. Synthesizing these traditionally plant-derived compounds in genetically modified yeast cells introduces the possibility of significantly reducing the total time and resources required for their production, and in turn, allows these valuable compounds to become cheaper and more readily available. Most biosynthesis pathways used in metabolic engineering applications have been discovered manually, requiring a tedious search of existing literature and metabolic databases. However, the recent rapid development of available metabolic information has enabled the development of automated approaches for identifying novel pathways. Computer-assisted pathfinding has the potential to save biochemists time in the initial discovery steps of metabolic engineering. In this paper, we review the parameters and heuristics used to guide the search in recent pathfinding algorithms. These parameters and heuristics capture information on the metabolic network structure, compound structures, reaction features, and organism-specificity of pathways. No one metabolic pathfinding algorithm or search parameter stands out as the best to use broadly for solving the pathfinding problem, as each method and parameter has its own strengths and shortcomings. As assisted pathfinding approaches continue to become more sophisticated, the development of better methods for visualizing pathway results and integrating these results into existing metabolic engineering practices is also important for encouraging wider use of these pathfinding methods.

Validation of the Version 1 NOAA/NASA Pathfinder Sea Surface Temperature Data Set

NASA Technical Reports Server (NTRS)

Smith, Elizabeth A.

1998-01-01

A high-resolution, global satellite-derived sea surface temperature (SST) data set called Pathfinder, from the Advanced Very High Resolution Radiometer (AVHRR) aboard the NOAA Polar Orbiters, is available from the Jet Propulsion Laboratory Physical Oceanography Distributed Active Archive Center (JPL PO.DAAC). Suitable for research as well as education, the Pathfinder SST data set is a result of a collaboration between the National Oceanographic and Atmospheric Administration (NOAA), the National Aeronautics and Space Administration (NASA) and investigators at several universities. NOAA and NASA are the sponsors of the Pathfinder Program, which takes advantage of currently archived Earth science data from satellites. Where necessary, satellite sensors have been intercalibrated, algorithms improved and processing procedures revised, in order to produce long time-series, global measurements of ocean, land and atmospheric properties necessary for climate research. Many Pathfinder data sets are available to researchers now, nearly a decade before the first launch of NASA's Earth Observing System (EOS). The lessons learned from the Pathfinder programs will facilitate the processing and management of terabytes of data from EOS. The Oceans component of Pathfinder has undertaken to reprocess all Global Area Coverage (GAC) data acquired by the 5-channel AVHRRs since 1981. The resultant data products are consistent and stably calibrated [Rao, 1993a, Rao, 1993b, Brown et al., 1993], Earth-gridded SST fields at a variety of spatial and temporal resolutions.

Pathfinder Instruments for Cloud and Aerosol Spaceborne Observations (PICASSO)

NASA Technical Reports Server (NTRS)

McCormick, M. Patrick; Winker, David M.

1998-01-01

This paper will describe the planned 3-year Pathfinder Instruments for Cloud and Aerosol Spaceborne Observations (PICASSO) mission, its instrumentation and implementation. It will use LITE and other data, plus analyses, to show the feasibility of such a mission. PICASSO is being proposed for NASA's Earth System Science Pathfinder (ESSP) program with launch predicted in 2003.

Pathfinder-Plus flight in Hawaii

NASA Technical Reports Server (NTRS)

2002-01-01

Pathfinder-Plus flight in Hawaii June 2002 AeroVironment's Pathfinder-Plus solar-powered flying wing recently flew a three-flight demonstration of its ability to relay third-generation cell phone and video signals as well as provide Internet linkage. The two pods underneath the center section of the wing carried the advanced two-way telecom package, developed by Japanese telecommunications interests.

Gambling on the Protestants: the Pathfinder Fund and birth control in Peru, 1958-1965.

PubMed

López, L Necochea

2014-01-01

Among the agencies involved in population control activities in the mid-twentieth century, none scored as many early victories in Latin America as did the Pathfinder Fund, founded by Procter & Gamble scion Clarence Gamble. This article analyzes a style in the delivery of family planning assistance in the developing world through the work of the Pathfinder Fund in Peru, the organization's hub in South America, and shows how Pathfinder personnel collaborated with local Protestant institutions. Its Protestant allies helped Pathfinder set up and manage rapid interventions such as the production of pamphlets, the smuggling of contraceptives, and the enrollment of physicians as advocates of the use of intrauterine devices. Although these rapid interventions helped quickly disseminate information and certain technologies among a fortunate few, they also weakened legitimate state agencies, neglected the monitoring of the safety of the drugs supplied, and alienated allies with their high-handed boldness.

LISA Pathfinder: An important first step towards a space-based gravitational wave observatory

NASA Astrophysics Data System (ADS)

Thorpe, James

2017-08-01

ESA's LISA Pathfinder mission was launched on Dec 3rd, 2015 and completed earlier this Summer. During this relatively short mission, Pathfinder at its two science payloads, Europe's LISA Technology Package and NASA's Disturbance Reduction System, demonstrated several techniques and technologies that enable development of a future space-based gravitational wave observatory. Most notably, Pathfinder demonstrated that the technique of drag-free flight could be utilized to place a test mass in near-perfect free-fall, with residual accelerations at the femto-g level in the milliHertz band. Additionally, technologies such as precision bonded optical structures for metrology, micropropulsion systems, and non-contact charge control, were successfully tested, retiring risk for LISA. In this talk, I will present an overview of Pathfinder's results to date and some perspective on how this success will be leveraged into realizing LISA.

Sojourner Sits Near Rock Garden

NASA Technical Reports Server (NTRS)

2003-01-01

The Mars Pathfinder Rover Sojourner is images by the Imager for Mars Pathfinder as it nears the rock 'Wedge.' Part of the Rock Garden is visible in the upper right of the image.

Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars over the next ten years. Mars Global Surveyor, already en route, arrives at Mars on September 11 to begin a two year orbital reconnaissance of the planet's composition, topography, and climate. Additional orbiters and landers will follow every 26 months.

The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Pathfinder aircraft flight #1

NASA Image and Video Library

1996-11-19

The Pathfinder research aircraft's solar cell arrays are prominently displayed as it touches down on the bed of Rogers Dry Lake at the Dryden Flight Research Center, Edwards, California, following a test flight. The solar arrays covered more than 75 percent of Pathfinder's upper wing surface, and provided electricity to power its six electric motors, flight controls, communications links and a host of scientific sensors.

Mars Pathfinder Landing Site Workshop

NASA Technical Reports Server (NTRS)

Golombek, Matthew (Editor)

1994-01-01

The Mars Pathfinder Project is an approved Discovery-class mission that will place a lander and rover on the surface of the Red Planet in July 1997. The Mars Pathfinder Landing Site Workshop was designed to allow the Mars scientific community to provide input as to where to land Pathfinder on Mars. The workshop was attended by over 60 people from around the United States and from Europe. Over 20 landing sites were proposed at the workshop, and the scientific questions and problems concerning each were addressed. The workshop and the discussion that occured during and afterward have significantly improved the ability to select a scientifically exciting but safe landing site on Mars.

Pathfinder aircraft flight #1

NASA Image and Video Library

1996-11-19

The Pathfinder solar-powered research aircraft settles in for landing on the bed of Rogers Dry Lake at the Dryden Flight Research Center, Edwards, California, after a successful test flight Nov. 19, 1996. The ultra-light craft flew a racetrack pattern at low altitudes over the flight test area for two hours while project engineers checked out various systems and sensors on the uninhabited aircraft. The Pathfinder was controlled by two pilots, one in a mobile control unit which followed the craft, the other in a stationary control station. Pathfinder, developed by AeroVironment, Inc., is one of several designs being evaluated under NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program.

Visible and Near-Infrared Properties of Optical Fibers Coupled to the Pathfinder High-Resolution NIR Spectrograph

NASA Astrophysics Data System (ADS)

McCoy, K.; Ramsey, L.

2011-09-01

The Penn State Astronomy and Astrophysics Department’s Pathfinder instrument is a fiber-fed, warm-bench echelle spectrograph designed to explore technical issues that must be resolved in order to measure precise radial velocities that will allow the detection of exoplanets in the near-infrared (NIR). In May 2010, Pathfinder demonstrated 10-20 m/s radial-velocity precision in the NIR at the 9 meter Hobby-Eberly Telescope. To attain even higher precision, we are investigating the NIR properties of the optical fibers that transmit light from the telescope to Pathfinder. We conducted a series of modal noise tests with visible and NIR laser diodes on a 200 micron diameter, fused-silica, multimode optical fiber as the preliminary step in analyzing the degrading effects of modal noise on radial-velocity precision. We report these test results and comment on our future tests to reduce the negative effects of modal noise and focal ratio degradation (FRD). The lessons learned from this research and the Pathfinder prototype will be used in Pathfinder II, which will aim to achieve better than 5 m/s in the NIR.

Protein O-Mannosyltransferases Affect Sensory Axon Wiring and Dynamic Chirality of Body Posture in the Drosophila Embryo.

PubMed

Baker, Ryan; Nakamura, Naosuke; Chandel, Ishita; Howell, Brooke; Lyalin, Dmitry; Panin, Vladislav M

2018-02-14

Genetic defects in protein O-mannosyltransferase 1 (POMT1) and POMT2 underlie severe muscular dystrophies. POMT genes are evolutionarily conserved in metazoan organisms. In Drosophila , both male and female POMT mutants show a clockwise rotation of adult abdominal segments, suggesting a chirality of underlying pathogenic mechanisms. Here we described and analyzed a similar phenotype in POMT mutant embryos that shows left-handed body torsion. Our experiments demonstrated that coordinated muscle contraction waves are associated with asymmetric embryo rolling, unveiling a new chirality marker in Drosophila development. Using genetic and live-imaging approaches, we revealed that the torsion phenotype results from differential rolling and aberrant patterning of peristaltic waves of muscle contractions. Our results demonstrated that peripheral sensory neurons are required for normal contractions that prevent the accumulation of torsion. We found that POMT mutants show abnormal axonal connections of sensory neurons. POMT transgenic expression limited to sensory neurons significantly rescued the torsion phenotype, axonal connectivity defects, and abnormal contractions in POMT mutant embryos. Together, our data suggested that protein O-mannosylation is required for normal sensory feedback to control coordinated muscle contractions and body posture. This mechanism may shed light on analogous functions of POMT genes in mammals and help to elucidate the etiology of neurological defects in muscular dystrophies. SIGNIFICANCE STATEMENT Protein O-mannosyltransferases (POMTs) are evolutionarily conserved in metazoans. Mutations in POMTs cause severe muscular dystrophies associated with pronounced neurological defects. However, neurological functions of POMTs remain poorly understood. We demonstrated that POMT mutations in Drosophila result in abnormal muscle contractions and cause embryo torsion. Our experiments uncovered a chirality of embryo movements and a unique POMT -dependent mechanism that maintains symmetry of a developing system affected by chiral forces. Furthermore, POMTs were found to be required for proper axon connectivity of sensory neurons, suggesting that O-mannosylation regulates the sensory feedback controlling muscle contractions. This novel POMT function in the peripheral nervous system may shed light on analogous functions in mammals and help to elucidate pathomechanisms of neurological abnormalities in muscular dystrophies. Copyright © 2018 the authors 0270-6474/18/381850-16$15.00/0.

Martian Surface & Pathfinder Airbags

NASA Image and Video Library

1997-07-05

This image of the Martian surface was taken in the afternoon of Mars Pathfinder's first day on Mars. Taken by the Imager for Mars Pathfinder (IMP camera), the image shows a diversity of rocks strewn in the foreground. A hill is visible in the distance (the notch within the hill is an image artifact). Airbags are seen at the lower right. http://photojournal.jpl.nasa.gov/catalog/PIA00612

JWST Pathfinder Telescope Integration

NASA Technical Reports Server (NTRS)

Matthews, Gary W.; Kennard, Scott H.; Broccolo, Ronald T.; Ellis, James M.; Daly, Elizabeth A.; Hahn, Walter G.; Amon, John N.; Mt. Pleasant, Stephen M.; Texter, Scott; Atkinson, Charles B.;

Sojourner, Wedge, & Shark

NASA Technical Reports Server (NTRS)

1997-01-01

This Imager for Mars Pathfinder (IMP) image taken near the end of daytime operations on Sol 50 shows the Sojourner rover between the rocks 'Wedge' (foreground) and 'Shark' (behind rover). The rover successfully deployed its Alpha Proton X-Ray Spectrometer on Shark on Sol 52.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Pathfinder aircraft liftoff on altitude record setting flight of 71,500 feet

NASA Image and Video Library

1997-07-07

The Pathfinder aircraft has set a new unofficial world record for high-altitude flight of over 71,500 feet for solar-powered aircraft at the U.S. Navy's Pacific Missile Range Facility, Kauai, Hawaii. Pathfinder was designed and manufactured by AeroVironment, Inc, of Simi Valley, California, and was operated by the firm under a jointly sponsored research agreement with NASA's Dryden Flight Research Center, Edwards, California. Pathfinder's record-breaking flight occurred July 7, 1997. The aircraft took off at 11:34 a.m. PDT, passed its previous record altitude of 67,350 feet at about 5:45 p.m. and then reached its new record altitude at 7 p.m. The mission ended with a perfect nighttime landing at 2:05 a.m. PDT July 8. The new record is the highest altitude ever attained by a propellor-driven aircraft. Before Pathfinder, the altitude record for propellor-driven aircraft was 67,028 feet, set by the experimental Boeing Condor remotely piloted aircraft.

Morning Martian Atmospheric Temperature Gradients and Fluctuations Observed by Mars Pathfinder

NASA Technical Reports Server (NTRS)

Mihalov, John D.; Haberle, R. M.; Murphy, J. R.; Seiff, A.; Wilson, G. R.

1999-01-01

We have studied the most prominent atmospheric temperature fluctuations observed during Martian mornings by Mars Pathfinder and have concluded, based on comparisons with wind directions, that they appear to be a result of atmospheric heating associated with the Lander spacecraft. Also, we have examined the morning surface layer temperature lapse rates, which are found to decrease as autumn approaches at the Pathfinder location, and which have mean (and median) values as large as 7.3 K/m in the earlier portions of the Pathfinder landed mission. It is plausible that brief isolated periods with gradients twice as steep are associated with atmospheric heating adjacent to Lander air bag material. In addition, we have calculated the gradient with height of the structure function obtained with Mars Pathfinder, for Mars' atmospheric temperatures measured within about 1.3 m from the surface, assuming a power law dependence, and have found that these gradients superficially resemble those reported for the upper region of the terrestrial stable boundary layer.

Mars Pathfinder Rover-Lewis Research Center Technology Experiments Program

NASA Technical Reports Server (NTRS)

Stevenson, Steven M.

1997-01-01

An overview of NASA's Mars Pathfinder Program is given and the development and role of three technology experiments from NASA's Lewis Research Center and carried on the Mars Pathfinder rover is described. Two recent missions to Mars were developed and managed by the Jet Propulsion Laboratory, and launched late last year: Mars Global Surveyor in November 1996 and Mars Pathfinder in December 1996. Mars Global Surveyor is an orbiter which will survey the planet with a number of different instruments, and will arrive in September 1997, and Mars Pathfinder which consists of a lander and a small rover, landing on Mars July 4, 1997. These are the first two missions of the Mars Exploration Program consisting of a ten year series of small robotic martian probes to be launched every 26 months. The Pathfinder rover will perform a number of technology and operational experiments which will provide the engineering information necessary to design and operate more complex, scientifically oriented surface missions involving roving vehicles and other machinery operating in the martian environment. Because of its expertise in space power systems and technologies, space mechanisms and tribology, Lewis Research Center was asked by the Jet Propulsion Laboratory, which is heading the Mars Pathfinder Program, to contribute three experiments concerning the effects of the martian environment on surface solar power systems and the abrasive qualities of the Mars surface material. In addition, rover static charging was investigated and a static discharge system of several fine Tungsten points was developed and fixed to the rover. These experiments and current findings are described herein.

Ventifacts at the Pathfinder landing site

USGS Publications Warehouse

Bridges, N.T.; Greeley, R.; Haldemann, A.F.C.; Herkenhoff, K. E.; Kraft, M.; Parker, T.J.; Ward, A.W.

1999-01-01

About half of the rocks at the Mars Pathfinder Ares Vallis landing site appear to be ventifacts, rocks abraded by windborne particles. Comparable resolution images taken by the Imager for Mars Pathfinder (IMP) camera and the Viking landers show that ventifacts are more abundant at the Pathfinder site. The ventifacts occur in several forms, including rocks with faceted edges, finger-like projections, elongated pits, flutes, grooves, and possible rills. The trends of elongated pits, flutes, grooves, and rills cluster at ???280-330?? clockwise from north and generally dip 10-30?? away from their trend direction. These orientations are indicative of southeast to northwest winds and differ from the trend of wind tails at the landing site, the direction of local wind streaks, and predictions of the Global Circulation Model, all of which indicate northeast to southwest winds. The disparity between these data sets strongly suggests that local circulation patterns have changed since the abrasion of the ventifacted rocks. The greater number of ventifacts at the Pathfinder site compared to either of the Viking sites is most easily explained as being due to a larger supply of abrading particles, composed of either sand-sized grains or indurated dust aggregates, and higher surface roughness, which should increase the momentum of saltating grains. The Pathfinder ventifacts may have formed shortly after the deposition of outflow channel sediments nearly 2 Gry ago, when a large local supply of abrading particles should have been abundant and atmospheric conditions may have been more conducive to rock abrasion from saltating grains. Based on how ventifacts form on Earth, the several ventifact forms seen at the Pathfinder site and their presence on some rocks but not on others are probably due to local airflow conditions, original rock shape, exposure duration, rock movement, and to a lesser extent, rock lithology. The abundance of ventifacts at the Pathfinder site, together with other evidence of weathering, indicates that unaltered rock surfaces are rare on Mars. Copyright 1999 by the American Geophysical Union.

Rocky terrain & airbags

NASA Technical Reports Server (NTRS)

1997-01-01

An area of very rocky terrain at the Ares Vallis landing site, along with the lander's deflated airbags, were imaged by the Imager for Mars Pathfinder (IMP) before its deployment on Sol 2. The metallic object at the bottom is a bracket for the IMP's release mechanism.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Sojourner's APXS at Shark

NASA Technical Reports Server (NTRS)

1997-01-01

The Sojourner rover is seen next to the rock 'Shark', in this image taken by the Imager for Mars Pathfinder (IMP) near the end of daytime operations on Sol 52. The rover's Alpha Proton X-Ray Spectrometer is deployed against the rock. The rock 'Wedge' is in the foreground.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

MOC's Highest Resolution View of Mars Pathfinder Landing Site

NASA Technical Reports Server (NTRS)

2000-01-01

[figure removed for brevity, see original site] (A) Mars Pathfinder site, left: April 1998; right: January 2000.

[figure removed for brevity, see original site] (B) top: April 1998; bottom: January 2000.

Can Mars Global Surveyor's 1.5 meter (5 ft) per pixel camera be used to find any evidence as to the fate of the Mars Polar Lander that was lost on December 3, 1999? One way to find out is to look for one of the other Mars landers and determine what, if anything, can be seen. There have been three successful Mars lander missions: Viking 1 (July 1976), Viking 2 (September 1976), and Mars Pathfinder (July 1997). Of these, the location of Mars Pathfinder is known the best because there are several distinct landmarks visible in the lander's images that help in locating the spacecraft. The MGS MOC Operations Team at Malin Space Science Systems has been tasked since mid-December 1999 with looking for the lost Polar Lander. Part of this effort has been to test the capabilities of MOC by taking a picture of the landing site of Mars Pathfinder.

An attempt to photograph the Pathfinder site was made once before, in April 1998, by turning the entire MGS spacecraft so that the camera could point at the known location of the Mars Pathfinder lander. Turning the MGS spacecraft like this is not a normal operation--it takes considerable planning, and disrupts the on-going, normal acquisition of science data. It took 3 attempts to succeed, but on April 22, 1998, MOC acquired the picture seen on the left side of Figure A, above. The three near-by major landmarks that were visible to the Pathfinder's cameras are labeled here (North Peak, Big Crater, Twin Peaks). It was known at the time that this image was not adequate to see the Pathfinder lander because the camera was not in focus and had a resolution of only 3.3 meters (11 ft) per pixel. In this and all other images shown here, north is up. All views of the 1998 MOC image are illuminated from the lower right, all views of the 2000 MOC image are illuminated from the lower left.

As part of the Polar Lander search effort, the Mars Pathfinder site was targeted again in December 1999 and January 2000. Like the 1998 attempt, the spacecraft had to be pointed off of its normal, nadir (straight-down) view. Like history repeating itself, it once again took 3 tries before the Pathfinder landing site was hit. The picture on the right side of Figure A, above, shows the new image that was acquired on January 16, 2000. The white box indicates the location shown in Figure B (above, right). The 1000 m scale bar equals 0.62 miles.

Figure B (above) shows a subsection of both the 1998 image (top, labeled SPO-1-25603) and the 2000 image (bottom, labeled m11-2414) projected at a scale of 3 meters (10 ft) per pixel. At this scale, the differences in camera focus and sunlight illumination angle are apparent, with the January 2000 image being both in focus and having better lighting conditions. In addition, the MGS spacecraft took the 2000 image from a lower altitude than in 1998, thus the image has better spatial resolution overall. The 500 m scale bar is equal to about 547 yards. The white box shows the location of images in Figure C, below.

[figure removed for brevity, see original site] (C) higher-resolution view; left: April 1998; right: January 2000.

[figure removed for brevity, see original site] D) Erroneous, preliminary identification of Mars Pathfinder location in January 2000 image. Subsequent analysis (Figures E & F, below) identified the correct spot.

The third figure (C, above) again shows portions of the April 1998 image (C, left) and January 2000 image (C, right), only this time they have been enlarged to a resolution of 0.75 meters (2.5 ft) per pixel. The intrinsic resolution of the January 2000 image is 1.5 meters (5 ft), so this is a 200% expanded view of the actual M11-02414 image. The circular features in this and the previous images are impact craters in various states of erosion. Some boulders (dark dots) can be seen near the crater in the lower left corner. The texture that runs diagonally across the scene from upper left toward lower right consists of ridges created by the giant floods that washed through the Pathfinder site from Ares and/or Tiu Vallis many hundreds of millions of years ago. These ridges and the troughs between them were also seen by the Pathfinder lander; their crests often covered with boulders and cobbles (which cannot be seen at the resolution of the MOC image). The 100 m scale bar is equal to 109 yards (which can be compared with a 100 yard U.S. football field). The Mars Pathfinder landing site is located near the center of this view.

The fourth picture, Figure D (above), shows a feature that was initially thought to be the Mars Pathfinder lander by MOC investigators. This and the following figures point out just how difficult it is to find a lander on the martian surface using the MGS MOC. Figure D was prepared early in the week following receipt of the new MOC image on January 17, 2000, and for several days it was believed that the lander had been found. As the subsequent two figures will show (E, and F, below), this location appears to be in error. How the features were misidentified is discussed below. Both Figure D and Figure F, showing possible locations of the Pathfinder lander in the MOC image, are enlarged by a factor of three over the intrinsic resolution of that image (that is, to a scale of 0.5 meters or about 1 ft, 7 inch per pixel). The right picture in Figure D shows sight-lines to the large horizon features--Big Crater, Twin Peaks, and North Peak--that were derived by the MOC team by looking at the images taken by the lander in 1997. After placing these lines on the overall image, there appeared to be two features close to the intersection of the sight-lines. Based upon the consistency of the size and shape of the lander as illuminated by sunlight in this image, the northern of the two candidate features (the small 'hump' at the center of both left and right pictures) was considered, at the time, to be the most likely. HOWEVER...

[figure removed for brevity, see original site] (E) Photoclinometry, Topography, and Revised Landing Site Location.

[figure removed for brevity, see original site] (F) Mars Pathfinder Landing Site; lander not resolved by MOC.

Later in the week following acquisition of the January 16, 2000, image (and over the following weekend), there was time for additional analysis to determine whether the rounded hump identified earlier in the week (Figure D, above) was, in fact, the Mars Pathfinder lander. A computer program that estimates relative topography in a MOC image from knowledge of the illumination (called 'shape-from-shading' or photoclinometry) was run to determine which parts of the landing site image are depressions, which are hills, and which are flat surfaces. The picture at the left in Figure E (above) shows the photoclinometry results for the area around the Pathfinder lander. The picture at the center of Figure E shows the same photoclinometry results overlain by an inset of a topographic map of the Pathfinder landing site derived by the U.S. Geological Survey Astrogeology Branch (Flagstaff, Arizona) from photogrammetry (parallax measurements) using images from Pathfinder's own stereo camera. By matching the features seen by MOC with those seen by the Pathfinder (the large arrows are examples of the matching), the location of the lander was refined and is now indicated in the picture on the right side of Figure E. The large, rounded hump previously identified as Pathfinder in Figure D (above), is more likely a large boulder that was seen in Pathfinder's images and named 'Couch' by the Pathfinder science team in 1997.

Figure F is summary of the results of this effort to find Mars Pathfinder: it shows that while the landing site of Mars Pathfinder can be identified, the lander itself cannot be seen. It is too small to be resolved in an image where each pixel acquired by the MOC covers a square of 1.5 meters (5 feet) to a side, given the contrast conditions on Mars and the MOC's ability to discriminate contrast. At this scale, Pathfinder is not much larger than two pixels, and the same is true of the lost Polar Lander.

No evidence has been found in the January 2000 MOC image of the aft portion of Mars Pathfinder's aeroshell or its parachute, either. If the aeroshell is laying on its side, as interpreted from Mars Pathfinder's images, then it would be very difficult to see this from orbit. Because Pathfinder did not image the parachute, it is not known how it may be configured on the surface--it could be wrapped around the aeroshell or a boulder, for example.

This effort to photograph the Mars Pathfinder lander demonstrates that it is extremely difficult to find a lander on the surface of Mars using the Mars Orbiter Camera aboard the MGS spacecraft. This analysis suggests that it is not very likely that the December 1999 Polar Lander will be found by MOC.

Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea

PubMed Central

Salehi, Pezhman; Gundimeda, Usha; Lael Cantu, Homero; Lavinsky, Joel; Myint, Anthony; Wang, Juemei; Abdala, Carolina; Ohyama, Takahiro; Coate, Thomas Matthew

2017-01-01

Neuropilin-1 (Nrp1) encodes the transmembrane cellular receptor neuropilin-1, which is associated with cardiovascular and neuronal development and was within the peak SNP interval on chromosome 8 in our prior GWAS study on age-related hearing loss (ARHL) in mice. In this study, we generated and characterized an inner ear-specific Nrp1 conditional knockout (CKO) mouse line because Nrp1 constitutive knockouts are embryonic lethal. In situ hybridization demonstrated weak Nrp1 mRNA expression late in embryonic cochlear development, but increased expression in early postnatal stages when cochlear hair cell innervation patterns have been shown to mature. At postnatal day 5, Nrp1 CKO mice showed disorganized outer spiral bundles and enlarged microvessels of the stria vascularis (SV) but normal spiral ganglion cell (SGN) density and presynaptic ribbon body counts; however, we observed enlarged SV microvessels, reduced SGN density, and a reduction of presynaptic ribbons in the outer hair cell region of 4-month-old Nrp1 CKO mice. In addition, we demonstrated elevated hearing thresholds of the 2-month-old and 4-month-old Nrp1 CKO mice at frequencies ranging from 4 to 32kHz when compared to 2-month-old mice. These data suggest that conditional loss of Nrp1 in the inner ear leads to progressive hearing loss in mice. We also demonstrated that mice with a truncated variant of Nrp1 show cochlear axon guidance defects and that exogenous semaphorin-3A, a known neuropilin-1 receptor agonist, repels SGN axons in vitro. These data suggest that Neuropilin-1/Semaphorin-3A signaling may also serve a role in neuronal pathfinding in the developing cochlea. In summary, our results here support a model whereby Neuropilin-1/Semaphorin-3A signaling is critical for the functional and morphological integrity of the cochlea and that Nrp1 may play a role in ARHL. PMID:29059194

Pathfinder aircraft taking off - setting new solar powered altitude record

NASA Image and Video Library

1995-09-11

The Pathfinder solar-powered remotely piloted aircraft climbs to a record-setting altitude of 50,567 feet during a flight Sept. 11, 1995, at NASA's Dryden Flight Research Center, Edwards, California. The flight was part of the NASA ERAST (Environmental Research Aircraft and Sensor Technology) program. The Pathfinder was designed and built by AeroVironment Inc., Monrovia, California. Solar arrays cover nearly all of the upper wing surface and produce electricity to power the aircraft's six motors.

MARS PATHFINDER INSPECTED BY ENGINEER LINDA ROBECK IN SAEF-2

NASA Technical Reports Server (NTRS)

1996-01-01

In the SAEF-2 spacecraft checkout facility, engineer Linda Robeck of the Jet Propulsion Laboratory inspects the Mars Pathfinder lander. The spacecraft arrived at Kennedy Space Center from Pasadena, CA on Aug. 13, 1996. The petals of the lander will be opened for checkout of the spacecraft and the installation of the small rover. Launch of Mars Pathfinder aboard a McDonnell Douglas Delta II rocket will occur from Pad B at Complex 17 on Dec. 2.

IGF-1 delivery to CNS attenuates motor neuron cell death but does not improve motor function in type III SMA mice.

PubMed

Tsai, Li-Kai; Chen, Yi-Chun; Cheng, Wei-Cheng; Ting, Chen-Hung; Dodge, James C; Hwu, Wuh-Liang; Cheng, Seng H; Passini, Marco A

2012-01-01

The efficacy of administering a recombinant adeno-associated virus (AAV) vector encoding human IGF-1 (AAV2/1-hIGF-1) into the deep cerebellar nucleus (DCN) of a type III SMA mouse model was evaluated. High levels of IGF-1 transcripts and protein were detected in the spinal cord at 2 months post-injection demonstrating that axonal connections between the cerebellum and spinal cord were able to act as conduits for the viral vector and protein to the spinal cord. Mice treated with AAV2/1-hIGF-1 and analyzed 8 months later showed changes in endogenous Bax and Bcl-xl levels in spinal cord motor neurons that were consistent with IGF-1-mediated anti-apoptotic effects on motor neurons. However, although AAV2/1-hIGF-1 treatment reduced the extent of motor neuron cell death, the majority of rescued motor neurons were non-functional, as they lacked axons that innervated the muscles. Furthermore, treated SMA mice exhibited abnormal muscle fibers, aberrant neuromuscular junction structure, and impaired performance on motor function tests. These data indicate that although CNS-directed expression of IGF-1 could reduce motor neuron cell death, this did not translate to improvements in motor function in an adult mouse model of type III SMA. Copyright © 2011 Elsevier Inc. All rights reserved.

Pathfinder aircraft flight #1

NASA Image and Video Library

1996-11-19

The Pathfinder solar-powered research aircraft is silhouetted against a clear blue sky as it soars aloft during a checkout flight from the Dryden Flight Research Center, Edwards, California, November, 1996.

Constraints and Approach for Selecting the Mars Surveyor '01 Landing Site

NASA Technical Reports Server (NTRS)

Golombek, M.; Bridges, N.; Gilmore, M.; Haldemann, A.; Parker, T.; Saunders, R.; Spencer, D.; Smith, J.; Weitz, C.

1999-01-01

There are many similarities between the Mars Surveyor '01 (MS '01) landing site selection process and that of Mars Pathfinder. The selection process includes two parallel activities in which engineers define and refine the capabilities of the spacecraft through design, testing and modeling and scientists define a set of landing site constraints based on the spacecraft design and landing scenario. As for Pathfinder, the safety of the site is without question the single most important factor, for the simple reason that failure to land safely yields no science and exposes the mission and program to considerable risk. The selection process must be thorough and defensible and capable of surviving multiple withering reviews similar to the Pathfinder decision. On Pathfinder, this was accomplished by attempting to understand the surface properties of sites using available remote sensing data sets and models based on them. Science objectives are factored into the selection process only after the safety of the site is validated. Finally, as for Pathfinder, the selection process is being done in an open environment with multiple opportunities for community involvement including open workshops, with education and outreach opportunities.

Constraints, Approach and Present Status for Selecting the Mars Surveyor 2001 Landing Site

NASA Technical Reports Server (NTRS)

Golombek, M.; Anderson, F.; Bridges, N.; Briggs, G.; Gilmore, M.; Gulick, V.; Haldemann, A.; Parker, T.; Saunders, R.; Spencer, D.;

MARS PATHFINDER CAMERA TEST IN SAEF-2

NASA Technical Reports Server (NTRS)

1996-01-01

In the Spacecraft Assembly and Encapsulation Facility-2 (SAEF-2), workers from the Jet Propulsion Laboratory (JPL) are conducting a systems test of the imager for the Mars Pathfinder. The imager (white and metallic cylindrical element close to hand of worker at left) is a specially designed camera featuring a stereo- imaging system with color capability provided by a set of selectable filters. It is mounted atop an extendable mast on the Pathfinder lander. Visible to the far left is the small rover which will be deployed from the lander to explore the Martian surface. Transmitting back to Earth images of the trail left by the rover will be one of the mission objectives for the imager. To the left of the worker standing near the imager is the mast for the low-gain antenna; the round high-gain antenna is to the right. Visible in the background is the cruise stage that will carry the Pathfinder on a direct trajectory to Mars. The Mars Pathfinder is one of two Mars-bound spacecraft slated for launch aboard Delta II expendable launch vehicles this year.

NASA's Chemical Transfer Propulsion Program for Pathfinder

NASA Technical Reports Server (NTRS)

Hannum, Ned P.; Berkopec, Frank D.; Zurawski, Robert L.

1989-01-01

Pathfinder is a research and technology project, with specific deliverables, initiated by the National Aeronautics and Space Administration (NASA) which will strengthen the technology base of the United States civil space program in preparation for future space exploration missions. Pathfinder begins in Fiscal Year 1989, and is to advance a collection of critical technologies for these missions and ensure technology readiness for future national decisions regarding exploration of the solar system. The four major thrusts of Pathfinder are: surface exploration, in-space operations, humans-in-space, and space transfer. The space transfer thrust will provide the critical technologies needed for transportation to, and return from, the Moon, Mars, and other planets in the solar system, as well as for reliable and cost-effective Earth-orbit operations. A key element of this thrust is the Chemical Transfer Propulsion program which will provide the propulsion technology for high performance, liquid oxygen/liquid hydrogen expander cycle engines which may be operated and maintained in space. Described here are the program overview including the goals and objectives, management, technical plan, and technology transfer for the Chemical Transfer Propulsion element of Pathfinder.

Free-Flight Experiments in LISA Pathfinder

NASA Technical Reports Server (NTRS)

Thorpe, J. I.; Cutler, C. J.; Hewitson, M.; Jennrich, O.; Maghami, P.; Paczkowski, S.; Russano, G.; Vitale, S.; Weber, W. J.

2014-01-01

The LISA Pathfinder mission will demonstrate the technology of drag-free test masses for use as inertial references in future space-based gravitational wave detectors. To accomplish this, the Pathfinder spacecraft will perform drag-free flight about a test mass while measuring the acceleration of this primary test mass relative to a second reference test mass. Because the reference test mass is contained within the same spacecraft, it is necessary to apply forces on it to maintain its position and attitude relative to the spacecraft. These forces are a potential source of acceleration noise in the LISA Pathfinder system that are not present in the full LISA configuration. While LISA Pathfinder has been designed to meet it's primary mission requirements in the presence of this noise, recent estimates suggest that the on-orbit performance may be limited by this 'suspension noise'. The drift-mode or free-flight experiments provide an opportunity to mitigate this noise source and further characterize the underlying disturbances that are of interest to the designers of LISA-like instruments. This article provides a high-level overview of these experiments and the methods under development to analyze the resulting data.

Preliminary Findings of the Photovoltaic Cell Calibration Experiment on Pathfinder Flight 95-3

NASA Technical Reports Server (NTRS)

Vargas-Aburto, Carlos

1997-01-01

The objective of the photovoltaic (PV) cell calibration experiment for Pathfinder was to develop an experiment compatible with an ultralight UAV to predict the performance of PV cells at AM0, the solar spectrum in space, using the Langley plot technique. The Langley plot is a valuable technique for this purpose and requires accurate measurements of air mass (pressure), cell temperature, solar irradiance, and current-voltage(IV) characteristics with the cells directed normal to the direct ray of the sun. Pathfinder's mission objective (95-3) of 65,000 ft. maximum altitude, is ideal for performing the Langley plot measurements. Miniaturization of electronic data acquisition equipment enabled the design and construction of an accurate and light weight measurement system that meets Pathfinder's low payload weight requirements.

Rover Soil Experiments Near Yogi

NASA Technical Reports Server (NTRS)

1997-01-01

Sojourner, while on its way to the rock Yogi, performed several soil mechanics experiments. Piles of loose material churned up from the experiment are seen in front of and behind the Rover. The rock Pop-Tart is visible near the front right rover wheel. Yogi is at upper right. The image was taken by the Imager for Mars Pathfinder.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Mars Pathfinder Landing Site and Surroundings

NASA Technical Reports Server (NTRS)

2007-01-01

NASA's Mars Pathfinder landed on Mars on July 4, 1997, and continued operating until Sept. 27 of that year. The landing site is on an ancient flood plain of the Ares and Tiu outflow channels. The High Resolution Imaging Science Experiment (HiRISE) camera on NASA's Mars Reconnaissance Orbiter took an image on Dec. 21, 2006, that provides unprecedented detail of the geology of the region and hardware on the surface.

[figure removed for brevity, see original site] HiRISE Image This is the entire image. The crater at center bottom was unofficially named 'Big Crater' by the Pathfinder team. Its wall was visible from Pathfinder, located 3 kilometers (2 miles) to the north. The two bright features to the upper left of Big Crater are the 'Twin Peaks,' also observed by Pathfinder. The bright mound to the upper right of the Twin Peaks is 'North Knob,' seen in Pathfinder images as peaking over the horizon.

At this scale there is no obvious geologic evidence of an ancient flood. Rather, impact craters dominate the scene, attesting to an old surface. The age is probably on the order of 1.8 billion to 3.5 billion years, when the Ares and Tiu floods are estimated to have occurred. Wind-formed linear ripples and dunes are seen throughout and are concentrated within craters. Sets of polygonal ridges of enigmatic origin are seen east of the Pathfinder lander. Rocks are visible over the entire image, with heavy concentrations near fresh-looking craters. Most of them are probably blocks tossed outward by crater-forming impacts.

The complete image is centered at 19.1 degrees north latitude, 326.8 degrees east longitude. The range to the target site was 284.7 kilometers (177.9 miles). At this distance the image scale is 28.5 centimeters (11 inches) per pixel, so objects about 85 centimeters (33 inches) across are resolved. The image shown here has been map-projected to 25 centimeters (10 inches) per pixel. North is up. The image was taken at a local Mars time of 3:35 p.m., and the scene is illuminated from the west with a solar incidence angle of 52 degrees, thus the sun was about 38 degrees above the horizon. At a solar longitude of 154.0 degrees, the season on Mars is northern summer.

[figure removed for brevity, see original site] Landing Site Region This is a close-up of the area in the vicinity of the Pathfinder landing site. Major features are named. The white box outlines the area of the image, discussed next, where hardware is seen.

[figure removed for brevity, see original site] Hardware on the Surface This image shows the Pathfinder lander on the surface. Zooming in, one can discern the ramps, science deck, and portions of the airbags on the Pathfinder lander. (See next image for closer view.) The back shell and parachute are to the south, and four features that may be portions of the heat shield are identified. Two of these were visible from Pathfinder. At the time of that mission, the nearest object was provisionally identified as the back shell. However, analysis of the HiRISE image and reinterpretation of Pathfinder images, plus an improved understanding of how hardware looks on the Martian surface based on ground-level and orbital images of the Mars Exploration Rover landing sites, indicate that the glint is bright enough that it may be insulating material from inside the heat shield. The back shell and parachute were out of sight behind a ridge from Pathfinder's ground view. One of the three bright features, identified as heat shield debris, was also identified during the Pathfinder mission.

[figure removed for brevity, see original site] [figure removed for brevity, see original site] Annotated Version Unannotated Version Topographic Map of Landing Site Region Portions of the HiRISE image are overlaid onto color-coded topographic maps constructed by the U.S. Geological Survey from stereo images acquired by the Imager for Mars Pathfinder on the lander. The white feature at the center is Pathfinder lander. The scales on the x and y axes are in meters, with the lander as the zero point. The color code for elevation relative to the lander is different in the left and right images, and shown in meters underneath each image. The correspondence between the overhead view revealed by HiRISE and the positions of topographic features inferred almost a decade ago from Pathfinder's horizontal view of the landscape is striking. The close-up on the right complements panoramas taken by the lander's camera, including the accompanying composite version showing the Sojourner rover at various locations it reached during the mission.

[figure removed for brevity, see original site] Mars Pathfinder Gallery Panorama This version of the Gallery Panorama taken with the lander's Imager for Mars Pathfinder camera shows many of the locations where the mission's Sojourner rover ended a Martian day during the 12-week mission. (There was only one Sojourner. The image is a composite.) One annotation indicates the last known position of Sojourner, near the rock 'Chimp,' at the time of the final data transmission from the lander. The location labeled 'Sojourner?' has been tentatively identified as the current position of the rover based on comparison of the ground-level view with the Dec. 21, 2006, image from NASA's Mars Reconnaissance Orbiter. At the proposed current location of the rover, a feature can be discerned in the 2006 orbital image that is about the right size for Sojourner and wasn't present when the Gallery Panorama was taken. Some rocks and other features that can be identified in the orbiter's high-resolution view are labeled in this ground-level view.

[figure removed for brevity, see original site] Topographic Perspective of Landing Site Region) This is a perspective view based on the topographic map and artificial color derived from Pathfinder and other data. The vertical scale is exaggerated by a factor of three, compared with horizontal dimensions. The white feature at center is the Pathfinder lander. It appears flat because the topographic map derived from the Imager for Mars Pathfinder data did not include the spacecraft itself.

Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyamoto, Yuki; Eguchi, Takahiro; Kawahara, Kazuko

Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationshipsmore » between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics. - Highlights: • The HLD4 mutant of HSPD1 decreases mitochondrial fission frequency. • The HLD4 mutant decreases mitochondrial fusion frequency. • Mitochondria harboring the HLD4 mutant exhibit slow motility. • The HLD4 mutant of HSPD1 decreases mitochondrial membrane potential. • HLD4-related diseases may be due to decreased mitochondrial dynamics.« less

MARS PATHFINDER LANDER REMOVED FROM SHIPPING CONTAINER IN SAEF-2

NASA Technical Reports Server (NTRS)

1996-01-01

In the SAEF-2 spacecraft checkout facility at Kennedy Space Center, engineers and technicians from Jet Propulsion Laboratory remove the Mars Pathfinder lander from its shipping container, still covered in protective wrapping. Pictured from L-R, Linda Robeck, Jerry Gutierrez, Lorraine Garcia, Chuck Foehlinger of JPL. The arrival of the spacecraft at KSC from Pasadena, CA occurred on Aug. 13, 1996. Launch of Mars Pathfinder aboard a McDonnell Douglas Delta II rocket will occur from Pad B at Complex 17 on Dec. 2.

Pathfinder aircraft in flight

NASA Image and Video Library

1995-07-27

The Pathfinder research aircraft's wing structure was clearly defined as it soared under a clear blue sky during a test flight July 27, 1995, from Dryden Flight Research Center, Edwards, California. The center section and outer wing panels of the aircraft had ribs constructed of thin plastic foam, while the ribs in the inner wing panels are fabricated from lightweight composite material. Developed by AeroVironment, Inc., the Pathfinder was one of several unmanned aircraft being evaluated under NASA's Environmental Research Aircraft and Sensor Technology (ERAST) program.

Mars Pathfinder Microrover- Implementing a Low Cost Planetary Mission Experiment

NASA Technical Reports Server (NTRS)

Matijevic, J.

1996-01-01

The Mars Pathfinder Microrover Flight Experiment (MFEX) is a NASA Office of Space Access and Technology (OSAT) flight experiment which has been delivered and integrated with the Mars Pathfinder (MPF) lander and spacecraft system. The total cost of the MFEX mission, including all subsystem design and development, test, integration with the MPF lander and operations on Mars has been capped at $25 M??is paper discusses the process and the implementation scheme which has resulted in the development of this first Mars rover.

MARS PATHFINDER AIR BAG INSTALLATION IN SAEF-2

NASA Technical Reports Server (NTRS)

1996-01-01

In the Spacecraft Assembly and Encapsulation Facility-2 (SAEF-2), the Jet Propulsion Laboratory (JPL) team installs air bags on the Mars Pathfinder lander. The four airbags will cushion the lander as it touches down on the Martian surface, protecting the delicate instruments and Surveyor small rover inside the tetrahedral-shaped lander. The Mars Pathfinder is one of two Mars-bound spacecraft being prepared for launch this fall. Liftoff is set for Dec. 2 at the beginning of a 24-day launch period.

Pathfinder Innovation Projects

EPA Pesticide Factsheets

The Pathfinder program supports high-risk, high-reward research ideas with funding and staff time. The goal is to feed a culture of innovation in the Agency and integrate innovative ideas in EPA research programs.

Immersive Environments for Mission Operations: Beyond Mars Pathfinder

NASA Technical Reports Server (NTRS)

Wright, J.; Hartman, F.; Cooper, B.

1998-01-01

Immersive environments are just beginning to be used to support mission operations at the Jet Propulsion Laboratory. This technology contributed to the Mars Pathfinder Mission in planning sorties for the Sojourner rover.

Pathfinder Innovation Projects: Awardees 2015

EPA Pesticide Factsheets

The Pathfinder program supports high-risk, high-reward research ideas with funding and staff time. The goal is to feed a culture of innovation in the Agency and integrate innovative ideas in EPA research programs.

Pathfinder Innovation Projects: Awardees 2016

EPA Pesticide Factsheets

The Pathfinder program supports high-risk, high-reward research ideas with funding and staff time. The goal is to feed a culture of innovation in the Agency and integrate innovative ideas in EPA research programs.

Photogrammetric analysis of horizon panoramas: The Pathfinder landing site in Viking orbiter images

USGS Publications Warehouse

Oberst, J.; Jaumann, R.; Zeitler, W.; Hauber, E.; Kuschel, M.; Parker, T.; Golombek, M.; Malin, M.; Soderblom, L.

1999-01-01

Tiepoint measurements, block adjustment techniques, and sunrise/sunset pictures were used to obtain precise pointing data with respect to north for a set of 33 IMP horizon images. Azimuth angles for five prominent topographic features seen at the horizon were measured and correlated with locations of these features in Viking orbiter images. Based on this analysis, the Pathfinder line/sample coordinates in two raw Viking images were determined with approximate errors of 1 pixel, or 40 m. Identification of the Pathfinder location in orbit imagery yields geological context for surface studies of the landing site. Furthermore, the precise determination of coordinates in images together with the known planet-fixed coordinates of the lander make the Pathfinder landing site the most important anchor point in current control point networks of Mars. Copyright 1999 by the American Geophysical Union.

Yogi the rock

NASA Technical Reports Server (NTRS)

1997-01-01

Yogi, a rock taller than rover Sojourner, is the subject of this image, taken by the deployed Imager for Mars Pathfinder (IMP) on Sol 3. The soil in the foreground will be the location of multiple soil mechanics experiments performed by Sojourner's cleated wheels. Pathfinder scientists will be able to control the force inflicted on the soil beneath the rover's wheels, giving them insight into the soil's mechanical properties.

The image was taken by the Imager for Mars Pathfinder (IMP) after its deployment on Sol 3. Mars Pathfinder was developed and managed by the Jet Propulsion Laboratory (JPL) for the National Aeronautics and Space Administration. JPL is an operating division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.

PubMed

Roy Chowdhury, Subir K; Smith, Darrell R; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A; Fernyhough, Paul

2012-06-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Mineralogic and compositional properties of Martian soil and dust: results from Mars Pathfinder

USGS Publications Warehouse

Bell, J.F.; McSween, H.Y.; Crisp, J.A.; Morris, R.V.; Murchie, S.L.; Bridges, N.T.; Johnson, J. R.; Britt, D.T.; Golombek, M.P.; Moore, H.J.; Ghosh, A.; Bishop, J.L.; Anderson, R.C.; Brückner, J.; Economou, T.; Greenwood, J.P.; Gunnlaugsson, H.P.; Hargraves, R.M.; Hviid, S.; Knudsen, J.M.; Madsen, M.B.; Reid, R.; Rieder, R.; Soderblom, L.

2000-01-01

Mars Pathfinder obtained multispectral, elemental, magnetic, and physical measurements of soil and dust at the Sagan Memorial Station during the course of its 83 sol mission. We describe initial results from these measurements, concentrating on multispectral and elemental data, and use these data, along with previous Viking, SNC meteorite, and telescopic results, to help constrain the origin and evolution of Martian soil and dust. We find that soils and dust can be divided into at least eight distinct spectral units, based on parameterization of Imager for Mars Pathfinder (IMP) 400 to 1000 nm multispectral images. The most distinctive spectral parameters for soils and dust are the reflectivity in the red, the red/blue reflectivity ratio, the near-IR spectral slope, and the strength of the 800 to 1000 nm absorption feature. Most of the Pathfinder spectra are consistent with the presence of poorly crystalline or nanophase ferric oxide(s), sometimes mixed with small but varying degrees of well-crystalline ferric and ferrous phases. Darker soil units appear to be coarser-grained, compacted, and/or mixed with a larger amount of dark ferrous materials relative to bright soils. Nanophase goethite, akaganeite, schwertmannite, and maghemite are leading candidates for the origin of the absorption centered near 900 nm in IMP spectra. The ferrous component in the soil cannot be well-constrained based on IMP data. Alpha proton X-ray spectrometer (APXS) measurements of six soil units show little variability within the landing site and show remarkable overall similarity to the average Viking-derived soil elemental composition. Differences exist between Viking and Pathfinder soils, however, including significantly higher S and Cl abundances and lower Si abundances in Viking soils and the lack of a correlation between Ti and Fe in Pathfinder soils. No significant linear correlations were observed between IMP spectral properties and APXS elemental chemistry. Attempts at constraining the mineralogy of soils and dust using normative calculations involving mixtures of smectites and silicate and oxide minerals did not yield physically acceptable solutions. We attempted to use the Pathfinder results to constrain a number of putative soil and dust formation scenarios, including palagonitization and acid-fog weathering. While the Pathfinder soils cannot be chemically linked to the Pathfinder rocks by palagonitization, this study and McSween et al. [1999] suggest that palagonitic alteration of a Martian basaltic rock, plus mixture with a minor component of locally derived andesitic rock fragments, could be consistent with the observed soil APXS and IMP properties.

Constraints, Approach, and Status of Mars Surveyor 2001 Landing Site Selection

NASA Technical Reports Server (NTRS)

Golombek, M.; Bridges, N.; Briggs, G.; Gilmore, M.; Haldemann, A.; Parker, T.; Saunders, R.; Spencer, D.; Smith, J.; Soderblom, L.

1999-01-01

There are many similarities between the Mars Surveyor '01 (MS '01) landing site selection process and that of Mars Pathfinder. The selection process includes two parallel activities in which engineers define and refine the capabilities of the spacecraft through design, testing and modeling and scientists define a set of landing site constraints based on the spacecraft design and landing scenario. As for Pathfinder, the safety of the site is without question the single most important factor, for the simple reason that failure to land safely yields no science and exposes the mission and program to considerable risk. The selection process must be thorough and defensible and capable of surviving multiple withering reviews similar to the Pathfinder decision. On Pathfinder, this was accomplished by attempting to understand the surface properties of sites using available remote sensing data sets and models based on them. Science objectives are factored into the selection process only after the safety of the site is validated. Finally, as for Pathfinder, the selection process is being done in an open environment with multiple opportunities for community involvement including open workshops, with education and outreach opportunities. Additional information is contained in the original extended abstract.

Yogi the rock - 3D

NASA Technical Reports Server (NTRS)

1997-01-01

Yogi, a rock taller than rover Sojourner, is the subject of this image, taken in stereo by the deployed Imager for Mars Pathfinder (IMP) on Sol 3. 3D glasses are necessary to identify surface detail. The soil in the foreground has been the location of multiple soil mechanics experiments performed by Sojourner's cleated wheels. Pathfinder scientists were able to control the force inflicted on the soil beneath the rover's wheels, giving them insight into the soil's mechanical properties. The soil mechanics experiments were conducted after this image was taken.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Click below to see the left and right views individually. [figure removed for brevity, see original site] Left [figure removed for brevity, see original site] Right

Operations and Autonomy of the Mars Pathfinder Microrover

NASA Technical Reports Server (NTRS)

Mishkin, A. H.; Morrison, J. C.; Nguyen, T. T.; Stone, H. W.; Cooper, B. K.

1998-01-01

The Microrover Flight Experiment (MFEX) is a NSAS OACT (Office of Advanced Concepts and Technology) flight experiment which, integrated with the Mars Pathfinder (MPF) lander and spacecraft system, landed on Mars on July 4, 1997.

Lithium-Thionyl Chloride Batteries for the Mars Pathfinder Microrover

NASA Technical Reports Server (NTRS)

Deligiannis, Frank; Frank, Harvey; Staniewicz, R. J.; Willson, John

1996-01-01

A discussion of the power requirements for the Mars Pathfinder Mission is given. Topics include: battery requirements; cell design; battery design; test descriptions and results. A summary of the results is also included.

Pathfinder on lakebed rolling out for test flight

NASA Image and Video Library

1995-12-10

The Pathfinder research aircraft's wing structure is clearly defined in this photo as personnel from AeroVironment rolled it out onto the lakebed at NASA's Dryden Flight Research Center, Edwards, California, for another test flight.

Simultaneous measurements of magnesium, calcium and sodium influxes in perfused squid giant axons under membrane potential control.

PubMed

Rojas, E; Taylor, R E

1975-10-01

1. Giant axons from the squids Dosidicus gigas, Loligo forbesi and Loligo vulgaris were internally perfused with 550 or 275 mM KF plus sucrose and bathed in artificial sea water containing 45Ca, 28Mg or mixtures of 45Ca-28Mg or 45Ca-22Na. Resting influxes and extra influxes during voltage-clamp pulses were measured by collecting and counting the internal perfusate. 2. For Dosidicus axons in 10 mM-CaCl2 the resting influx of calcium was 0-016 +/- 0-007 p-mole/cm2 sec and a linear function of external concentration. For two experiments in 10 and 84-7 mM-CaCl2, 100 nM tetrodotoxin had no effect. Resting calcium influx in 10 mM-CaCl2 was 0-017 +/- 0-013 p-mole/cm2 sec for Loligo axons. 3. With 55 mM-MgCl2 outside the average resting magnesium influx was 0-124 +/- 0-080 p-mole/cm2 sec for Loligo axons. Discarding one aberrant point the value is 0-105 +/- 0-046 which is not significantly different from the resting calcium influx for Dosidicus fibres in 55 mM-CaCl2, given as 0-094 p-mole/cm2 sec by the regression line shown in Fig. 1. In two experiments 150 nM tetrodotoxin had no effect. 4. With 430 mM-NaCl outside 100 nM tetrodotoxin reduced the average resting influx of sodium in Dosidicus axon from 27-7 +/- 4-5 to 25-1 +/- 6-2 p-mole/cm2 sec and for Loligo fibres in 460 mM-NaCl from 50-5 +/- 4 to 20 +/- 8 p-mole/cm2 sec. 5. Using depolarizing pulses of various durations, the extra calcium influx occurred in two phases. The early phase was eliminated by external application of tetrodotoxin. The results of analysis are consistent with, but do not rigorously demonstrate, the conclusion that the tetrodotoxin sensitive calcium entry is flowing through the normal sodium channels (cf. Baker, Hodgkin & Ridgway, 1971). 6. Measurements of extra influxes using 22Na and 45Ca simultaneously indicate that the time courses of tetrodotoxin sensitive calcium and sodium entry are similar but not necessarily identical. It is very doubtful that any significant calcium entry occurs before the sodium or is involved in the activation of the sodium system. 7. These measurements confirm for Loligo, as previously shown for Dosidicus axons, that the magnitude and time course of the sodium entry during a depolarizing pulse deduced from electrical measurements is the same as that measured with 22Na. 8. Using 28Mg, or mixtures of 45Ca and 28Mg, we observed a single phase of magnesium entry which was insensitive to external tetrodotoxin or internal tetraethyl ammonium. The magnitude of the magnesium influx was considerably greater than the calcium extra entry and large enough to have been detected in the experiments of Meves & Vogel (1973) if it represented current. 9. We suggest the possibility that the calcium and magnesium extra influxes, after external treatment with tetrodotoxin, during a depolarizing pulse, do not contribute to the measured current.

Simultaneous measurements of magnesium, calcium and sodium influxes in perfused squid giant axons under membrane potential control.

PubMed Central

Rojas, E; Taylor, R E

1975-01-01

1. Giant axons from the squids Dosidicus gigas, Loligo forbesi and Loligo vulgaris were internally perfused with 550 or 275 mM KF plus sucrose and bathed in artificial sea water containing 45Ca, 28Mg or mixtures of 45Ca-28Mg or 45Ca-22Na. Resting influxes and extra influxes during voltage-clamp pulses were measured by collecting and counting the internal perfusate. 2. For Dosidicus axons in 10 mM-CaCl2 the resting influx of calcium was 0-016 +/- 0-007 p-mole/cm2 sec and a linear function of external concentration. For two experiments in 10 and 84-7 mM-CaCl2, 100 nM tetrodotoxin had no effect. Resting calcium influx in 10 mM-CaCl2 was 0-017 +/- 0-013 p-mole/cm2 sec for Loligo axons. 3. With 55 mM-MgCl2 outside the average resting magnesium influx was 0-124 +/- 0-080 p-mole/cm2 sec for Loligo axons. Discarding one aberrant point the value is 0-105 +/- 0-046 which is not significantly different from the resting calcium influx for Dosidicus fibres in 55 mM-CaCl2, given as 0-094 p-mole/cm2 sec by the regression line shown in Fig. 1. In two experiments 150 nM tetrodotoxin had no effect. 4. With 430 mM-NaCl outside 100 nM tetrodotoxin reduced the average resting influx of sodium in Dosidicus axon from 27-7 +/- 4-5 to 25-1 +/- 6-2 p-mole/cm2 sec and for Loligo fibres in 460 mM-NaCl from 50-5 +/- 4 to 20 +/- 8 p-mole/cm2 sec. 5. Using depolarizing pulses of various durations, the extra calcium influx occurred in two phases. The early phase was eliminated by external application of tetrodotoxin. The results of analysis are consistent with, but do not rigorously demonstrate, the conclusion that the tetrodotoxin sensitive calcium entry is flowing through the normal sodium channels (cf. Baker, Hodgkin & Ridgway, 1971). 6. Measurements of extra influxes using 22Na and 45Ca simultaneously indicate that the time courses of tetrodotoxin sensitive calcium and sodium entry are similar but not necessarily identical. It is very doubtful that any significant calcium entry occurs before the sodium or is involved in the activation of the sodium system. 7. These measurements confirm for Loligo, as previously shown for Dosidicus axons, that the magnitude and time course of the sodium entry during a depolarizing pulse deduced from electrical measurements is the same as that measured with 22Na. 8. Using 28Mg, or mixtures of 45Ca and 28Mg, we observed a single phase of magnesium entry which was insensitive to external tetrodotoxin or internal tetraethyl ammonium. The magnitude of the magnesium influx was considerably greater than the calcium extra entry and large enough to have been detected in the experiments of Meves & Vogel (1973) if it represented current. 9. We suggest the possibility that the calcium and magnesium extra influxes, after external treatment with tetrodotoxin, during a depolarizing pulse, do not contribute to the measured current. PMID:1202193

A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders.

PubMed

Reinhard, Sarah M; Razak, Khaleel; Ethell, Iryna M

2015-01-01

The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called 'critical periods.' MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer's disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders.

The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes.

PubMed

McMacken, Grace; Cox, Dan; Roos, Andreas; Müller, Juliane; Whittaker, Roger; Lochmüller, Hanns

2018-05-01

Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective β2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via β2 adrenoceptors and via a cAMP-dependent pathway.

The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes

PubMed Central

McMacken, Grace; Cox, Dan; Roos, Andreas; Müller, Juliane; Whittaker, Roger; Lochmüller, Hanns

2018-01-01

Abstract Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective β2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via β2 adrenoceptors and via a cAMP-dependent pathway. PMID:29462491

Processing and Analysis of Mars Pathfinder Science Data at JPL's Science Data Processing Section

NASA Technical Reports Server (NTRS)

LaVoie, S.; Green, W.; Runkle, A.; Alexander, D.; Andres, P.; DeJong, E.; Duxbury, E.; Freda, D.; Gorjian, Z.; Hall, J.;

Sojourner Sits Near "Rock Garden"

NASA Image and Video Library

2003-02-01

The Mars Pathfinder Rover Sojourner images by the Imager for Mars Pathfinder as it nears the rock "Wedge." Part of the Rock Garden is visible in the upper right of the image. http://photojournal.jpl.nasa.gov/catalog/PIA04318

Analysis of Mars Pathfinder Entry Data, Aerothermal Heating, and Heat Shield Material Response

NASA Technical Reports Server (NTRS)

Milos, Frank; Chen, Y. K.; Tran, H. K.; Rasky, Daniel J. (Technical Monitor)

1997-01-01

The Mars Pathfinder heatshield contained several thermocouples and resistance thermometers. A description of the experiment, the entry data, and analysis of the entry environment and material response is presented. In particular, the analysis addresses uncertainties of the data and the fluid dynamics and material response models. The calculations use the latest trajectory and atmosphere reconstructions for the Pathfinder entry. A modified version of the GIANTS code is used for CFD (computational fluid dynamics) analyses, and FIAT is used for material response. The material response and flowfield are coupled appropriately. Three different material response models are considered. The analysis of Pathfinder entry data for validation of aerothermal heating and material response models is complicated by model uncertainties and unanticipated data-acquisition and processing problems. We will discuss these issues as well as ramifications of the data and analysis for future Mars missions.

Pathfinder technologies for bold new missions. [U.S. research and development program for space exploration

NASA Technical Reports Server (NTRS)

Sadin, Stanley R.; Rosen, Robert

1987-01-01

Project Pathfinder is a proposed U.S. Space Research and Technology program intended to enable bold new missions of space exploration. Pathfinder continues the advancement of technological capabilities and extends the foundation established under the Civil Space Technology Initiative, CSTI. By filling critical technological gaps, CSTI enhances access to Earth orbit and supports effective operations and science missions therein. Pathfinder, with a longer-term horizon, looks to a future that builds on Shuttle and Space Station and addresses technologies that support a range of exploration missions including: a return to the Moon to build an outpost; piloted missions to Mars; and continued scientific exploration of Earth and the other planets. The program's objective is to develop, within reasonable time frames, those emerging and innovative technologies that will make possible both new and enhanced missions and system concepts.

Shark

NASA Technical Reports Server (NTRS)

1997-01-01

This false color composite image from the Pathfinder lander shows the rock 'Shark' at upper right (Shark is about 0.69 m wide, 0.40 m high, and 6.4 m from the lander). The rock looks like a conglomerate in Sojourner rover images, but only the large elements of its surface textures can be seen here. This demonstrates the usefulness of having a robot rover geologist able to examine rocks up close.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

AVHRR-Based Polar Pathfinder Products: Evaluation, Enhancement and Transition to MODIS

NASA Technical Reports Server (NTRS)

Fowler, Charles; Masalanik, James; Stone, Robert; Stroeve, Julienne; Emery, William

2001-01-01

The Advanced Very High Resolution Radiometer (AVHRR)-Based Polar Pathfinder (APP) products include calibrated AVHRR channel data, surface temperatures, albedo, satellite scan and solar geometries, and cloud mask, all composited into twice-per-day images, and daily averaged fields of sea ice motion, for regions poleward of 50 latitude. Our general goals under this grant: (1) Quantify the APP accuracy and sources of error by comparing Pathfinder products with field measurements; (2) Determine the consistency of mean fields and trends in comparison with longer time series of available station data and forecast model output; (3) Investigate the consistency of the products between the different AVHRR instruments over the 1982-present period of the NOAA program; and (4) Compare and annual cycle of the APP products with MODIS to establish a baseline for extending Pathfinder-type products into the new ESE period.

Modeling to Mars: a NASA Model Based Systems Engineering Pathfinder Effort

NASA Technical Reports Server (NTRS)

Phojanamongkolkij, Nipa; Lee, Kristopher A.; Miller, Scott T.; Vorndran, Kenneth A.; Vaden, Karl R.; Ross, Eric P.; Powell, Bobby C.; Moses, Robert W.

2017-01-01

The NASA Engineering Safety Center (NESC) Systems Engineering (SE) Technical Discipline Team (TDT) initiated the Model Based Systems Engineering (MBSE) Pathfinder effort in FY16. The goals and objectives of the MBSE Pathfinder include developing and advancing MBSE capability across NASA, applying MBSE to real NASA issues, and capturing issues and opportunities surrounding MBSE. The Pathfinder effort consisted of four teams, with each team addressing a particular focus area. This paper focuses on Pathfinder team 1 with the focus area of architectures and mission campaigns. These efforts covered the timeframe of February 2016 through September 2016. The team was comprised of eight team members from seven NASA Centers (Glenn Research Center, Langley Research Center, Ames Research Center, Goddard Space Flight Center IV&V Facility, Johnson Space Center, Marshall Space Flight Center, and Stennis Space Center). Collectively, the team had varying levels of knowledge, skills and expertise in systems engineering and MBSE. The team applied their existing and newly acquired system modeling knowledge and expertise to develop modeling products for a campaign (Program) of crew and cargo missions (Projects) to establish a human presence on Mars utilizing In-Situ Resource Utilization (ISRU). Pathfinder team 1 developed a subset of modeling products that are required for a Program System Requirement Review (SRR)/System Design Review (SDR) and Project Mission Concept Review (MCR)/SRR as defined in NASA Procedural Requirements. Additionally, Team 1 was able to perform and demonstrate some trades and constraint analyses. At the end of these efforts, over twenty lessons learned and recommended next steps have been identified.

Disturbance Reduction System Thrusters Stabilize LISA Pathfinder

NASA Image and Video Library

2015-12-03

The LISA Pathfinder spacecraft is on its way to space, having successfully launched from Kourou, French Guiana Dec. 3, 2015. On board is the state-of-the-art Disturbance Reduction System DRS, a thruster technology developed at NASA JPL.

Dark Energy and Gravity Experiment Explorer and Pathfinder

NASA Astrophysics Data System (ADS)

Chiow, S.-w.; Yu, N.

2018-02-01

We propose to utilize the unique gravity and vacuum environment in the orbits of the Deep Space Gateway for direct detections of dark energy using atom interferometers, and for pathfinder experiments for future gravitational wave and dark matter detections.

A High-Throughput Screening Method for Small-Molecule Inhibitors of the Aberrant Mutant SOD1 and Dynein Complex Interaction

PubMed Central

Tang, Xiaohu; Seyb, Kathleen I.; Huang, Mickey; Schuman, Eli R.; Shi, Ping; Zhu, Haining; Glicksman, Marcie A.

2013-01-01

Aberrant protein-protein interactions are attractive drug targets in a variety of neurodegenerative diseases due to the common pathology of accumulation of protein aggregates. In amyotrophic lateral sclerosis, mutations in SOD1 cause the formation of aggregates and inclusions that may sequester other proteins and disrupt cellular processes. It has been demonstrated that mutant SOD1, but not wild-type SOD1, interacts with the axonal transport motor dynein and that this interaction contributes to motor neuron cell death, suggesting that disrupting this interaction may be a potential therapeutic target. However, it can be challenging to configure a high-throughput screening (HTS)–compatible assay to detect inhibitors of a protein-protein interaction. Here we describe the development and challenges of an HTS for small-molecule inhibitors of the mutant SOD1-dynein interaction. We demonstrate that the interaction can be formed by coexpressing the A4V mutant SOD1 and dynein intermediate complex in cells and that this interaction can be disrupted by compounds added to the cell lysates. Finally, we show that some of the compounds identified from a pilot screen to inhibit the protein-protein interaction with this method specifically disrupt the interaction between the dynein complex and mtSOD1 but not the dynein complex itself when applied to live cells. PMID:22140121

Modis, SeaWIFS, and Pathfinder funded activities

NASA Technical Reports Server (NTRS)

Evans, Robert H.

1995-01-01

MODIS (Moderate Resolution Imaging Spectrometer), SeaWIFS (Sea-viewing Wide Field Sensor), Pathfinder, and DSP (Digital Signal Processor) objectives are summarized. An overview of current progress is given for the automatic processing database, client/server status, matchup database, and DSP support.

Design Overview of the DM Radio Pathfinder Experiment

NASA Technical Reports Server (NTRS)

Silva-Feaver, Maximiliano; Chaudhuri, Saptarshi; Cho, Hsaio-Mei; Dawson, Carl; Graham, Peter; Irwin, Kent; Kuenstner, Stephen; Li, Dale; Mardon, Jeremy; Moseley, Harvey;

"Roadrunner Flats"

NASA Image and Video Library

1997-10-14

This enhanced color image of the Pathfinder landing site shows the eastern horizon. The elongated, reddish, low contrast region in the distance is "Roadrunner Flats." This image was taken by the Imager for Mars Pathfinder (IMP). Sojourner spent 83 days of a planned seven-day mission exploring the Martian terrain, acquiring images, and taking chemical, atmospheric and other measurements. The final data transmission received from Pathfinder was at 10:23 UTC on September 27, 1997. Although mission managers tried to restore full communications during the following five months, the successful mission was terminated on March 10, 1998. http://photojournal.jpl.nasa.gov/catalog/PIA00979

Strategy for selecting Mars Pathfinder landing sites

NASA Technical Reports Server (NTRS)

Greeley, Ronald; Kuzmin, Ruslin O.

1994-01-01

A strategy for Pathfinder site selection must be developed that is fundamentally different from most previous considerations. At least two approaches can be identified. In one approach, the objective is to select a site representing a key geologic unit on Mars, i.e., a unit that is widespread, easily recognized, and used frequently as a datum in various investigations. The second approach is to select a site that potentially affords access to a wide variety of rock types. Because rover range is limited, rocks from a variety of sources must be assembled in a small area for sampling. Regardless of the approach taken in site selection, the Pathfinder site should include eolian deposits and provisions should be made to obtain measurements on soils. A recommended approach for selecting the Mars Pathfinder landing site is to identify a deltaic deposit, composed of sediments derived from sources of various ages and geologic units that shows evidence of eolian activity. The site should be located as close as possible to the part of the outwash where rapid deposition occurred because the likelihood of 'sorting' by size and composition increases with distance, decreasing the probability of heterogeneity. In addition, it is recommended that field operation tests be conducted to gain experience and insight into conducting science with Pathfinder.

The SLIT/ROBO pathway: a regulator of cell function with implications for the reproductive system

PubMed Central

Dickinson, Rachel E; Duncan, W Colin

2010-01-01

The secreted SLIT glycoproteins and their Roundabout (ROBO) receptors were originally identified as important axon guidance molecules. They function as a repulsive cue with an evolutionarily conserved role in preventing axons from migrating to inappropriate locations during the assembly of the nervous system. In addition the SLIT-ROBO interaction is involved in the regulation of cell migration, cell death and angiogenesis and, as such, has a pivotal role during the development of other tissues such as the lung, kidney, liver and breast. The cellular functions that the SLIT/ROBO pathway controls during tissue morphogenesis are processes that are dysregulated during cancer development. Therefore inactivation of certain SLITs and ROBOs is associated with advanced tumour formation and progression in disparate tissues. Recent research has indicated that the SLIT/ROBO pathway could also have important functions in the reproductive system. The fetal ovary expresses most members of the SLIT and ROBO families. The SLITs and ROBOs also appear to be regulated by steroid hormones and regulate physiological cell functions in adult reproductive tissues such as the ovary and endometrium. Furthermore several SLITs and ROBOs are aberrantly expressed during the development of ovarian, endometrial, cervical and prostate cancer. This review will examine the roles this pathway could have in the development, physiology and pathology of the reproductive system and highlight areas for future research that could further dissect the influence of the SLIT/ROBO pathway in reproduction. PMID:20100881

The SLIT-ROBO pathway: a regulator of cell function with implications for the reproductive system.

PubMed

Dickinson, Rachel E; Duncan, W Colin

2010-04-01

The secreted SLIT glycoproteins and their Roundabout (ROBO) receptors were originally identified as important axon guidance molecules. They function as a repulsive cue with an evolutionarily conserved role in preventing axons from migrating to inappropriate locations during the assembly of the nervous system. In addition the SLIT-ROBO interaction is involved in the regulation of cell migration, cell death and angiogenesis and, as such, has a pivotal role during the development of other tissues such as the lung, kidney, liver and breast. The cellular functions that the SLIT/ROBO pathway controls during tissue morphogenesis are processes that are dysregulated during cancer development. Therefore inactivation of certain SLITs and ROBOs is associated with advanced tumour formation and progression in disparate tissues. Recent research has indicated that the SLIT/ROBO pathway could also have important functions in the reproductive system. The fetal ovary expresses most members of the SLIT and ROBO families. The SLITs and ROBOs also appear to be regulated by steroid hormones and regulate physiological cell functions in adult reproductive tissues such as the ovary and endometrium. Furthermore several SLITs and ROBOs are aberrantly expressed during the development of ovarian, endometrial, cervical and prostate cancer. This review will examine the roles this pathway could have in the development, physiology and pathology of the reproductive system and highlight areas for future research that could further dissect the influence of the SLIT/ROBO pathway in reproduction.

Developmental and adult-specific processes contribute to de novo neuromuscular regeneration in the lizard tail.

PubMed

Tokuyama, Minami A; Xu, Cindy; Fisher, Rebecca E; Wilson-Rawls, Jeanne; Kusumi, Kenro; Newbern, Jason M

2018-01-15

Peripheral nerves exhibit robust regenerative capabilities in response to selective injury among amniotes, but the regeneration of entire muscle groups following volumetric muscle loss is limited in birds and mammals. In contrast, lizards possess the remarkable ability to regenerate extensive de novo muscle after tail loss. However, the mechanisms underlying reformation of the entire neuromuscular system in the regenerating lizard tail are not completely understood. We have tested whether the regeneration of the peripheral nerve and neuromuscular junctions (NMJs) recapitulate processes observed during normal neuromuscular development in the green anole, Anolis carolinensis. Our data confirm robust axonal outgrowth during early stages of tail regeneration and subsequent NMJ formation within weeks of autotomy. Interestingly, NMJs are overproduced as evidenced by a persistent increase in NMJ density 120 and 250 days post autotomy (DPA). Substantial Myelin Basic Protein (MBP) expression could also be detected along regenerating nerves indicating that the ability of Schwann cells to myelinate newly formed axons remained intact. Overall, our data suggest that the mechanism of de novo nerve and NMJ reformation parallel, in part, those observed during neuromuscular development. However, the prolonged increase in NMJ number and aberrant muscle differentiation hint at processes specific to the adult response. An examination of the coordinated exchange between peripheral nerves, Schwann cells, and newly synthesized muscle of the regenerating neuromuscular system may assist in the identification of candidate molecules that promote neuromuscular recovery in organisms incapable of a robust regenerative response. Copyright © 2017 Elsevier Inc. All rights reserved.

Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice.

PubMed

Uribe, Valeria; Wong, Bibiana K Y; Graham, Rona K; Cusack, Corey L; Skotte, Niels H; Pouladi, Mahmoud A; Xie, Yuanyun; Feinberg, Konstantin; Ou, Yimiao; Ouyang, Yingbin; Deng, Yu; Franciosi, Sonia; Bissada, Nagat; Spreeuw, Amanda; Zhang, Weining; Ehrnhoefer, Dagmar E; Vaid, Kuljeet; Miller, Freda D; Deshmukh, Mohanish; Howland, David; Hayden, Michael R

2012-05-01

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.

Abnormal brain connectivity in first-episode psychosis: A diffusion MRI tractography study of the corpus callosum

PubMed Central

Price, Gary; Cercignani, Mara; Parker, Geoffrey J.M.; Altmann, Daniel R.; Barnes, Thomas R.E.; Barker, Gareth J.; Joyce, Eileen M.; Ron, Maria A.

2007-01-01

A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the clinical manifestations of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail and we present here a study of patients with first-episode psychosis using this technique. We selected the corpus callosum for this study because there is evidence that it is abnormal in schizophrenia. In addition, the topographical organization of its fibers makes it possible to relate focal abnormalities to specific cortical regions. Eighteen patients with first-episode psychosis and 21 healthy subjects took part in the study. A probabilistic tractography algorithm (PICo) was used to study fractional anisotropy (FA). Seed regions were placed in the genu and splenium to track fiber tracts traversing these regions, and a multi-threshold approach to study the probability of connection was used. Multiple linear regressions were used to explore group differences. FA, a measure of tract coherence, was reduced in tracts crossing the genu, and to a lesser degree the splenium, in patients compared with controls. FA was also lower in the genu in females across both groups, but there was no gender-by-group interaction. The FA reduction in patients may be due to aberrant myelination or axonal abnormalities, but the similar tract volumes in the two groups suggest that severe axonal loss is unlikely at this stage of the illness. PMID:17275337

Observing the cell in its native state: Imaging subcellular dynamics in multicellular organisms.

PubMed

Liu, Tsung-Li; Upadhyayula, Srigokul; Milkie, Daniel E; Singh, Ved; Wang, Kai; Swinburne, Ian A; Mosaliganti, Kishore R; Collins, Zach M; Hiscock, Tom W; Shea, Jamien; Kohrman, Abraham Q; Medwig, Taylor N; Dambournet, Daphne; Forster, Ryan; Cunniff, Brian; Ruan, Yuan; Yashiro, Hanako; Scholpp, Steffen; Meyerowitz, Elliot M; Hockemeyer, Dirk; Drubin, David G; Martin, Benjamin L; Matus, David Q; Koyama, Minoru; Megason, Sean G; Kirchhausen, Tom; Betzig, Eric

2018-04-20

True physiological imaging of subcellular dynamics requires studying cells within their parent organisms, where all the environmental cues that drive gene expression, and hence the phenotypes that we actually observe, are present. A complete understanding also requires volumetric imaging of the cell and its surroundings at high spatiotemporal resolution, without inducing undue stress on either. We combined lattice light-sheet microscopy with adaptive optics to achieve, across large multicellular volumes, noninvasive aberration-free imaging of subcellular processes, including endocytosis, organelle remodeling during mitosis, and the migration of axons, immune cells, and metastatic cancer cells in vivo. The technology reveals the phenotypic diversity within cells across different organisms and developmental stages and may offer insights into how cells harness their intrinsic variability to adapt to different physiological environments. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

S-adenosylmethionine levels regulate the Schwann cell DNA methylome

PubMed Central

Varela-Rey, Marta; Iruarrizaga-Lejarreta, Marta; Lozano, Juan José; Aransay, Ana María; Fernandez, Agustín F.; Lavin, José Luis; Mósen-Ansorena, David; Berdasco, María; Turmaine, Marc; Luka, Zigmund; Wagner, Conrad; Lu, Shelly C.; Esteller, Manel; Mirsky, Rhona; Jessen, Kristján R.; Fraga, Mario F.; Martínez-Chantar, María L.; Mato, José M.; Woodhoo, Ashwin

2014-01-01

SUMMARY Axonal myelination is essential for rapid saltatory impulse conduction in the nervous system, and malformation or destruction of myelin sheaths leads to motor and sensory disabilities. DNA methylation is an essential epigenetic modification during mammalian development, yet its role in myelination remains obscure. Here, using high-resolution methylome maps, we show that DNA methylation could play a key gene regulatory role in peripheral nerve myelination and that S-adenosylmethionine (SAMe), the principal methyl donor in cytosine methylation, regulates the methylome dynamics during this process. Our studies also point to a possible role of SAMe in establishing the aberrant DNA methylation patterns in a mouse model of diabetic neuropathy, implicating SAMe in the pathogenesis of this disease. These critical observations establish a link between SAMe and DNA methylation status in a defined biological system, and provides a novel mechanism that could direct methylation changes during cellular differentiation and in diverse pathological situations. PMID:24607226

Rock Abrasion on Mars: Clues from the Pathfinder and Viking Landing Sites

NASA Technical Reports Server (NTRS)

Bridges, N. T.; Parker, T. J.; Kramer, G. M.

2000-01-01

A significant discovery of the Mars Pathfinder (MPF) mission was that many rocks exhibit characteristics of ventifacts, rocks that have been sculpted by saltating particles. Diagnostic features identifying the rocks as ventifacts am elongated pits, flutes, and grooves (collectively referred to as "flutes" unless noted otherwise). Faceted rocks or rock portions, circular pits, rills, and possibly polished rock surfaces are also seen and could be due, to aeolian abrasion. Many of these features were initially identified in rover images, where spatial resolution generally exceeded that of the IMP (Imager for Mars Pathfinder) camera. These images had two major limitations: 1) Only a limited number of rocks were viewed by the rover, biasing flute statistics; and 2) The higher resolution obtained by the rover images and the lack of such pictures at the Viking landing sites hampered comparisons of rock morphologies between the Pathfinder and Viking sites. To avoid this problem, rock morphology and ventifact statistics have been examined using new "super-resolution" IMP and Viking Lander images. Analyses of these images show that: 1) Flutes are seen on about 50% or more of the rocks in the near field at the MPF site; 2) The orientation of these flutes is similar to that for flutes identified in rover images; and 3) Ventifacts are significantly more abundant at the Pathfinder landing site than at the two Viking Landing sites, where rocks have undergone only a limited amount of aeolian abrasion. This is most likely due to the ruggedness of the Pathfinder site and a greater supply of abrading particles available shortly after the Arcs and Tiu Valles outflow channel floods.

Results of the Imager for Mars Pathfinder windsock experiment

USGS Publications Warehouse

Sullivan, R.; Greeley, R.; Kraft, M.; Wilson, G.; Golombek, M.; Herkenhoff, K.; Murphy, J.; Smith, P.

2000-01-01

The Imager for Mars Pathfinder (IMP) windsock experiment measured wind speeds at three heights within 1.2 m of the Martian surface during Pathfinder landed operations. These wind data allowed direct measurement of near-surface wind profiles on Mars for the first time, including determination of aerodynamic roughness length and wind friction speeds. Winds were light during periods of windsock imaging, but data from the strongest breezes indicate aerodynamic roughness length of 3 cm at the landing site, with wind friction speeds reaching 1 m/s. Maximum wind friction speeds were about half of the threshold-of-motion friction speeds predicted for loose, fine-grained materials on smooth Martian terrain and about one third of the threshold-of-motion friction speeds predicted for the same size particles over terrain with aerodynamic roughness of 3 cm. Consistent with this, and suggesting that low wind speeds prevailed when the windsock array was not imaged and/or no particles were available for aeolian transport, no wind-related changes to the surface during mission operations have been recognized. The aerodynamic roughness length reported here implies that proposed deflation of fine particles around the landing site, or activation of duneforms seen by IMP and Sojourner, would require wind speeds >28 m/s at the Pathfinder top windsock height (or >31 m/s at the equivalent Viking wind sensor height of 1.6 m) and wind speeds >45 m/s above 10 m. These wind speeds would cause rock abrasion if a supply of durable particles were available for saltation. Previous analyses indicate that the Pathfinder landing site probably is rockier and rougher than many other plains units on Mars, so aerodynamic roughness length elsewhere probably is less than the 3-cm value reported for the Pathfinder site. Copyright 2000 by the American Geophysical Union.

Differential effects of myostatin deficiency on motor and sensory axons.

PubMed

Jones, Maria R; Villalón, Eric; Northcutt, Adam J; Calcutt, Nigel A; Garcia, Michael L

2017-12-01

Deletion of myostatin in mice (MSTN -/- ) alters structural properties of peripheral axons. However, properties like axon diameter and myelin thickness were analyzed in mixed nerves, so it is unclear whether loss of myostatin affects motor, sensory, or both types of axons. Using the MSTN -/- mouse model, we analyzed the effects of increasing the number of muscle fibers on axon diameter, myelin thickness, and internode length in motor and sensory axons. Axon diameter and myelin thickness were increased in motor axons of MSTN -/- mice without affecting internode length or axon number. The number of sensory axons was increased without affecting their structural properties. These results suggest that motor and sensory axons establish structural properties by independent mechanisms. Moreover, in motor axons, instructive cues from the neuromuscular junction may play a role in co-regulating axon diameter and myelin thickness, whereas internode length is established independently. Muscle Nerve 56: E100-E107, 2017. © 2017 Wiley Periodicals, Inc.

Curricular/Instructional Technology Resources.

ERIC Educational Resources Information Center

Roy, Loriene, Comp.

Part of a larger report on the Four Directions Project, an American Indian technology innovation project, this section includes 10 "pathfinders" to locating information on learning and instructional technology resources. The pathfinders were designed by students in the Graduate School of Library and Information Science at the University…

Internet Technology Resources.

ERIC Educational Resources Information Center

Roy, Loriene, Comp.

Part of a larger report on the Four Directions Project, an American Indian technology innovation project, this section includes six "pathfinders" to locating information on Internet resources. The pathfinders were designed by students in the Graduate School of Library and Information Science at the University of Texas at Austin in…

Cultural Themes.

ERIC Educational Resources Information Center

Roy, Loriene, Comp.

Part of a larger report on the Four Directions Project, an American Indian technology innovation project, this section includes 10 "pathfinders" to locating information on Native American cultural themes. The pathfinders were designed by students in the Graduate School of Library and Information Science at the University of Texas at…

Correspondence and Least Squares Analyses of Soil and Rock Compositions for the Viking Lander 1 and Pathfinder Sites

NASA Technical Reports Server (NTRS)

Larsen, K. W.; Arvidson, R. E.; Jolliff, B. L.; Clark, B. C.

2000-01-01

Correspondence and Least Squares Mixing Analysis techniques are applied to the chemical composition of Viking 1 soils and Pathfinder rocks and soils. Implications for the parent composition of local and global materials are discussed.

Sunset over Twin Peaks

NASA Technical Reports Server (NTRS)

1997-01-01

This image was taken by the Imager for Mars Pathfinder (IMP) about one minute after sunset on Mars on Sol 21. The prominent hills dubbed 'Twin Peaks' form a dark silhouette at the horizon, while the setting sun casts a pink glow over the darkening sky. The image was taken as part of a twilight study which indicates how the brightness of the sky fades with time after sunset. Scientists found that the sky stays bright for up to two hours after sunset, indicating that Martian dust extends very high into the atmosphere.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Pre-Dawn Martian Sky

NASA Technical Reports Server (NTRS)

1997-01-01

On Sol 39 there were wispy blue clouds in the pre-dawn sky of Mars, as seen by the Imager for Mars Pathfinder (IMP). The color image was made by taking blue, green, and red images and then combining them into a single color image. The clouds appear to have a bluish side and a greenish side because they moved (in the wind from the northeast) between images. This picture was made an hour and twenty minutes before sunrise -- the sun is not shining directly on the water ice clouds, but they are illuminated by the dawn twilight.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Wind effects on Martian soil

NASA Technical Reports Server (NTRS)

1997-01-01

This false-color combination image highlights details of wind effects on the Martian soil at the Pathfinder landing site. Red and blue filter images have been combined to enhance brightness contrasts among several soil units. Martian winds have distributed these lighter and darker fine materials in complex patterns around the rocks in the scene (blue). For scale, the rock at right center is 16 centimeters (6.3 inches) long. This scene is one of several that will be monitored weekly for changes caused by wind activity.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages and Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Soil disturbance by airbags

NASA Technical Reports Server (NTRS)

1997-01-01

Disturbance of the drift at the Pathfinder landing site reveals a shallow subsurface that is slightly darker but has similar spectral properties. The top set of images, in true color, shows the soils disturbed by the last bounce of the lander on its airbags before coming to rest and the marks created by retraction of the airbags. In the bottom set of images color differences have been enhanced. The mast at center is the Atmospheric Structure Instrument/Meteorology Package (ASI/MET). The ASI/MET is an engineering subsytem that acquired atmospheric data during Pathfinder's descent, and will continue to get more data through the entire landed mission. A shadow of the ASI/MET appears on a rock at left.

Mars Pathfinder was developed and managed by the Jet Propulsion Laboratory (JPL) for the National Aeronautics and Space Administration. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Atmosphere Processing Module Automation and Catalyst Durability Analysis for Mars ISRU Pathfinder

NASA Technical Reports Server (NTRS)

Petersen, Elspeth M.

2016-01-01

The Mars In-Situ Resource Utilization Pathfinder was designed to create fuel using components found in the planet’s atmosphere and regolith for an ascension vehicle to return a potential sample return or crew return vehicle from Mars. The Atmosphere Processing Module (APM), a subunit of the pathfinder, uses cryocoolers to isolate and collect carbon dioxide from Mars simulant gas. The carbon dioxide is fed with hydrogen into a Sabatier reactor where methane is produced. The APM is currently undergoing the final stages of testing at Kennedy Space Center prior to process integration testing with the other subunits of the pathfinder. The automation software for the APM cryocoolers was tested and found to perform nominally. The catalyst used for the Sabatier reactor was investigated to determine the factors contributing to catalyst failure. The results from the catalyst testing require further analysis, but it appears that the rapid change in temperature during reactor start up or the elevated operating temperature is responsible for the changes observed in the catalyst.

Distributed Active Archive Center

NASA Technical Reports Server (NTRS)

Bodden, Lee; Pease, Phil; Bedet, Jean-Jacques; Rosen, Wayne

1993-01-01

The Goddard Space Flight Center Version 0 Distributed Active Archive Center (GSFC V0 DAAC) is being developed to enhance and improve scientific research and productivity by consolidating access to remote sensor earth science data in the pre-EOS time frame. In cooperation with scientists from the science labs at GSFC, other NASA facilities, universities, and other government agencies, the DAAC will support data acquisition, validation, archive and distribution. The DAAC is being developed in response to EOSDIS Project Functional Requirements as well as from requirements originating from individual science projects such as SeaWiFS, Meteor3/TOMS2, AVHRR Pathfinder, TOVS Pathfinder, and UARS. The GSFC V0 DAAC has begun operational support for the AVHRR Pathfinder (as of April, 1993), TOVS Pathfinder (as of July, 1993) and the UARS (September, 1993) Projects, and is preparing to provide operational support for SeaWiFS (August, 1994) data. The GSFC V0 DAAC has also incorporated the existing data, services, and functionality of the DAAC/Climate, DAAC/Land, and the Coastal Zone Color Scanner (CZCS) Systems.

PATHFINDER: Probing Atmospheric Flows in an Integrated and Distributed Environment

NASA Technical Reports Server (NTRS)

Wilhelmson, R. B.; Wojtowicz, D. P.; Shaw, C.; Hagedorn, J.; Koch, S.

1995-01-01

PATHFINDER is a software effort to create a flexible, modular, collaborative, and distributed environment for studying atmospheric, astrophysical, and other fluid flows in the evolving networked metacomputer environment of the 1990s. It uses existing software, such as HDF (Hierarchical Data Format), DTM (Data Transfer Mechanism), GEMPAK (General Meteorological Package), AVS, SGI Explorer, and Inventor to provide the researcher with the ability to harness the latest in desktop to teraflop computing. Software modules developed during the project are available in the public domain via anonymous FTP from the National Center for Supercomputing Applications (NCSA). The address is ftp.ncsa.uiuc.edu, and the directory is /SGI/PATHFINDER.

Disturbing Pop-Tart

NASA Technical Reports Server (NTRS)

1997-01-01

The Sojourner rover's front right camera imaged Pop-tart, a small rock or indurated soil material which was pushed out of the surrounding drift material by Sojourner's front left wheel during a soil mechanics experiment.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Pathfinder: A Retrospective

NASA Technical Reports Server (NTRS)

Landis, Geoffrey A.; Lyons, Valerie (Technical Monitor)

2002-01-01

Mars is one of the most interesting planets in the solar system, featuring enormous canyons, giant volcanoes, and indications that, early in its history, it might have had rivers and perhaps even oceans. Five years ago, in July of 1997, the Pathfinder mission landed on Mars, bringing with it the microwave-oven sized Sojourner rover to wander around on the surface and analyse rocks. Among the experiments on the mission was one designed to analyse dust deposition. Pathfinder is only the first of an armada of spacecraft which will examine Mars from the pole to the equator in the next decade, culminating with a mission to bring humans to Mars.

Holographic beam mapping of the CHIME pathfinder array

NASA Astrophysics Data System (ADS)

Berger, Philippe; Newburgh, Laura B.; Amiri, Mandana; Bandura, Kevin; Cliche, Jean-François; Connor, Liam; Deng, Meiling; Denman, Nolan; Dobbs, Matt; Fandino, Mateus; Gilbert, Adam J.; Good, Deborah; Halpern, Mark; Hanna, David; Hincks, Adam D.; Hinshaw, Gary; Höfer, Carolin; Johnson, Andre M.; Landecker, Tom L.; Masui, Kiyoshi W.; Mena Parra, Juan; Oppermann, Niels; Pen, Ue-Li; Peterson, Jeffrey B.; Recnik, Andre; Robishaw, Timothy; Shaw, J. Richard; Siegel, Seth; Sigurdson, Kris; Smith, Kendrick; Storer, Emilie; Tretyakov, Ian; Van Gassen, Kwinten; Vanderlinde, Keith; Wiebe, Donald

2016-08-01

The Canadian Hydrogen Intensity Mapping Experiment (CHIME) Pathfinder radio telescope is currently surveying the northern hemisphere between 400 and 800 MHz. By mapping the large scale structure of neutral hydrogen through its redshifted 21 cm line emission between z 0.8-2.5 CHIME will contribute to our understanding of Dark Energy. Bright astrophysical foregrounds must be separated from the neutral hydrogen signal, a task which requires precise characterization of the polarized telescope beams. Using the DRAO John A. Galt 26 m telescope, we have developed a holography instrument and technique for mapping the CHIME Pathfinder beams. We report the status of the instrument and initial results of this effort.

Pathfinder, v6 n6, Nov/Dec 2008. Foundation Data and Technology

DTIC Science & Technology

2008-12-01

Geospatial-Intelligence Agency,Office of Corporate Communications,4600 Sangamore Road ,Bethesda,MD, 20816 -5003 8. PERFORMING ORGANIZATION REPORT...Communications 4600 Sangamore Road, Mail Stop D-54 Bethesda, MD 20816 -5003 Telephone: (301) 227-7388, DSN 287-7388 E-mail: pathfinder@nga.mil

A Pathfinder for Animal Research and Animal Rights.

ERIC Educational Resources Information Center

Anderson, David C.

1992-01-01

This pathfinder was originally prepared for "Biomedical Research and Animal Rights," a session sponsored by the Veterinary Medical Libraries and Research Libraries Sections of the Medical Library Association. Current resources are described, from bibliographies to electronic bulletin boards, which relate to the issue of laboratory animal…

Is it feasible to pool funds for local children's services in England? Evidence from the national evaluation of children's trust pathfinders.

PubMed

Lorgelly, Paula; Bachmann, Max; Shreeve, Ann; Reading, Richard; Thorburn, June; Mugford, Miranda; O'Brien, Margaret; Husbands, Chris

2009-01-01

To describe how funds were pooled or otherwise jointly managed by National Health Service (NHS) primary care trusts and local authorities in England. To compare expenditure on local children's services by health, education and social services. We conducted a questionnaire survey of all 35 children's trust pathfinders, six months after they were launched, with a follow-up at 2.5 years. We also undertook an in-depth analysis of local authorities and primary care trusts, within eight pathfinder areas and three non-pathfinder areas, whereby we compared expenditure on children's services, interviewed managers and professionals and examined financial documents. Local authorities and NHS trusts coordinated expenditure in various ways, most commonly through informal agreements and aligning budgets but also by formally pooling budgets. The latter were usually for selected services such as child and adolescent mental health services, though four children's trusts pathfinders pooled (or aligned) their budgets for all children's services. Total expenditure per child was greatest for education, lowest for social services and intermediate for health. However, it was difficult to quantify education expenditure on children with health and social care needs, and health care expenditure on children. Sharing money for local children's services requires shared objectives, trust, and legal and accounting expertise. Several different mechanisms are permitted and many are feasible but programme budgeting for children's services could make them more effective.

Mitochondria localize to injured axons to support regeneration

PubMed Central

Han, Sung Min; Baig, Huma S.; Hammarlund, Marc

2016-01-01

SUMMARY Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons, so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration. Experimental alterations to axonal mitochondrial distribution or mitochondrial respiratory chain function result in corresponding changes to regeneration outcomes. Axonal mitochondria are specifically required for growth cone migration, identifying a key energy challenge for injured neurons. Finally, mitochondrial localization to the axon after injury is regulated in part by dual-leucine zipper kinase-1 (DLK-1), a conserved regulator of axon regeneration. These data identify regulation of axonal mitochondria as a new cell biological mechanism that helps determine the regenerative response of injured neurons. PMID:28009276

Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis

PubMed Central

Zambonin, Jessica L.; Zhao, Chao; Ohno, Nobuhiko; Campbell, Graham R.; Engeham, Sarah; Ziabreva, Iryna; Schwarz, Nadine; Lee, Sok Ee; Frischer, Josa M.; Turnbull, Doug M.; Trapp, Bruce D.; Lassmann, Hans; Franklin, Robin J. M.

2011-01-01

Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in experimental demyelination and remyelination in vivo and in vitro are consistent with a partial amelioration of the supposed increase in energy demand of demyelinated axons by remyelination. PMID:21705418

Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis.

PubMed

Zambonin, Jessica L; Zhao, Chao; Ohno, Nobuhiko; Campbell, Graham R; Engeham, Sarah; Ziabreva, Iryna; Schwarz, Nadine; Lee, Sok Ee; Frischer, Josa M; Turnbull, Doug M; Trapp, Bruce D; Lassmann, Hans; Franklin, Robin J M; Mahad, Don J

2011-07-01

Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in experimental demyelination and remyelination in vivo and in vitro are consistent with a partial amelioration of the supposed increase in energy demand of demyelinated axons by remyelination.

Creatine pretreatment protects cortical axons from energy depletion in vitro

PubMed Central

Shen, Hua; Goldberg, Mark P.

2012-01-01

Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6 mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24 h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2 h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. PMID:22521466

The Pathfinder Microrover

NASA Technical Reports Server (NTRS)

Matijevic, J. R.; Bickler, D. B.; Braun, D. F.; Eisen, H. J.; Matthies, L. H.; Mishkin, A. H.; Stone, H. W.; van Nieuwstadt, L. M.; Wen, L. C.; Wilcox, B. H.;

Pathfinders: An Intellectual Guide to Libraries.

ERIC Educational Resources Information Center

Jung, Claudia Ruediger; And Others

Intended as an example for other college libraries, this collection of 38 pathfinders and bibliographies was developed by the reference staff of the Calvin Coolidge Library at Castleton State College, Vermont. Designed to present the types of literature available in particular subject fields and those works readily available in the Coolidge…

Pathfinder Teaching and Learning Units.

ERIC Educational Resources Information Center

Hawaii Univ., Honolulu. Sea Grant Program.

This collection of teaching units were selected from materials developed during the Operation Pathfinder Institutes (OPI) which took place in the Pacific region between 1994 and 1999. The institutes were intended to provide upper elementary and middle school science teachers with an opportunity to develop a deeper understanding of the marine…

Sedimentary geomorphology of the Mars Pathfinder Landing Site

NASA Technical Reports Server (NTRS)

Rice, James W., Jr.; Parker, Timothy Jay

1997-01-01

The first landing on Mars in over 20 years will take place July 4, 1997, near te mouth of the Ares Vallis outflow channel located in southeastern Chryse Planitia. Mars Pathfinder, unlike Viking 1, is expected to land on a surface that has a distinct and unambiguous fluvial signature.

Teacher Job Satisfaction: Lessons from the TSW Pathfinder Project

ERIC Educational Resources Information Center

Butt, Graham; Lance, Ann; Fielding, Antony; Gunter, Helen; Rayner, Steve; Thomas, Hywel

2005-01-01

Government policy assumes that modernization and remodelling will be effective as external intervention mechanisms to improve job satisfaction. Based on data collected as part of the evaluation of the "Transforming the School Workforce Pathfinder Project", an argument is presented here which suggests that internal management models may…

Airbag Retraction

NASA Image and Video Library

1997-07-05

This image shows that the Mars Pathfinder airbags have been successfully retracted, allowing safe deployment of the rover ramps. The Sojourner rover is at lower right, and rocks are visible in the background. Mars Pathfinder landed successfully on the surface of Mars today at 10:07 a.m. PDT. http://photojournal.jpl.nasa.gov/catalog/PIA00618

Pathfinders on Black Dance in America.

ERIC Educational Resources Information Center

Roy, Loriene, Ed.

This is a compilation of 18 pathfinders (i.e., a bibliographic instruction aid) on black dance in America, prepared by graduate students in the "Information Resources in the Humanities" and the "Information Resources in the Social Sciences" classes in the Graduate School of Library and Information Science at the University of…

Mechanical design of the Mars Pathfinder mission

NASA Technical Reports Server (NTRS)

Eisen, Howard Jay; Buck, Carl W.; Gillis-Smith, Greg R.; Umland, Jeffrey W.

1997-01-01

The Mars Pathfinder mission and the Sojourner rover is reported on, with emphasis on the various mission steps and the performance of the technologies involved. The mechanical design of mission hardware was critical to the success of the entry sequence and the landing operations. The various mechanisms employed are considered.

Pathfinder, Volume 7. Number 4, Jul/Aug 2009. GEOINT in Action

DTIC Science & Technology

2009-08-01

Rd,Bethesda,MD, 20816 -5003 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S...Communications 4600 Sangamore Road, Mail Stop D-39 Bethesda, MD 20816 -5003 Telephone: (301) 227-7388, DSN 287-7388 E-mail: pathfinder@nga.mil

Pathfinder, v6 n3, May/Jun 2008. Unifying the Intelligence Profession

DTIC Science & Technology

2008-06-01

ADDRESS(ES) National Geospatial-Intelligence Agency,Office of Corporate Communications,4600 Sangamore Road ,Bethesda,MD, 20816 -5003 8. PERFORMING...Sangamore Road, Mail Stop D-54 Bethesda, MD 20816 -5003 Telephone: (301) 227-7388, DSN 287-7388 E-mail: pathfinder@nga.mil Director Vice Adm. Robert

Pathfinder, v6 n5, Sep/Oct 2008. Shielding Our Home and Nation

DTIC Science & Technology

2008-10-01

Agency,Office of Corporate Communications,4600 Sangamore Road ,Bethesda,MD, 20816 -5003 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING... 20816 -5003 Telephone: (301) 227-7388, DSN 287-7388 E-mail: pathfinder@nga.mil Director Vice Adm. Robert B. Murrett, U.S. Navy Deputy Director

The Twin Peaks in 3-D, as Viewed by the Mars Pathfinder IMP Camera

NASA Image and Video Library

1997-11-04

Twin Peaks are modest-size hills to the southwest of NASA Mars Pathfinder landing site. They were discovered on the first panoramas taken by the IMP camera on the 4th of July, 1997. 3D glasses are necessary to identify surface detail.

Intracellular calcium release through IP3R or RyR contributes to secondary axonal degeneration.

PubMed

Orem, Ben C; Pelisch, Nicolas; Williams, Joshua; Nally, Jacqueline M; Stirling, David P

2017-10-01

Severed CNS axons often retract or dieback away from the injury site and fail to regenerate. The precise mechanisms underlying acute axonal dieback and secondary axonal degeneration remain poorly understood. Here we investigate the role of Ca 2+ store mediated intra-axonal Ca 2+ release in acute axonal dieback and secondary axonal degeneration. To differentiate between primary (directly transected) and "bystander" axonal injury (axons spared by the initial injury but then succumb to secondary degeneration) in real-time we use our previously published highly focal laser-induced spinal cord injury (LiSCI) ex vivo model. Ascending spinal cord dorsal column axons that express YFP were severed using an 800 nm laser pulse while being imaged continuously using two-photon excitation microscopy. We inhibited two major intra-axonal Ca 2+ store channels, ryanodine receptors (RyR) and IP 3 R, with ryanodine or 2-APB, respectively, to individually determine their role in axonal dieback and secondary axonal degeneration. Each antagonist was dissolved in artificial CSF and applied 1h post-injury alone or in combination, and continuously perfused for the remainder of the imaging session. Initially following LiSCI, transected axons retracted equal distances both distal and proximal to the lesion. However, by 4h after injury, the distal axonal segments that are destined for Wallerian degeneration had significantly retracted further than their proximal counterparts. We also found that targeting either RyR or IP 3 R using pharmacological and genetic approaches significantly reduced proximal axonal dieback and "bystander" secondary degeneration of axons compared to vehicle controls at 6h post-injury. Combined treatment effects on secondary axonal degeneration were similar to either drug in isolation. Together, these results suggest that intra-axonal Ca 2+ store mediated Ca 2+ release through RyR or IP 3 R contributes to secondary axonal degeneration following SCI. Copyright © 2017 Elsevier Inc. All rights reserved.

Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function.

PubMed

Cioni, Jean-Michel; Wong, Hovy Ho-Wai; Bressan, Dario; Kodama, Lay; Harris, William A; Holt, Christine E

2018-03-07

The axons of retinal ganglion cells (RGCs) are topographically sorted before they arrive at the optic tectum. This pre-target sorting, typical of axon tracts throughout the brain, is poorly understood. Here, we show that cytoplasmic FMR1-interacting proteins (CYFIPs) fulfill non-redundant functions in RGCs, with CYFIP1 mediating axon growth and CYFIP2 specifically involved in axon sorting. We find that CYFIP2 mediates homotypic and heterotypic contact-triggered fasciculation and repulsion responses between dorsal and ventral axons. CYFIP2 associates with transporting ribonucleoprotein particles in axons and regulates translation. Axon-axon contact stimulates CYFIP2 to move into growth cones where it joins the actin nucleating WAVE regulatory complex (WRC) in the periphery and regulates actin remodeling and filopodial dynamics. CYFIP2's function in axon sorting is mediated by its binding to the WRC but not its translational regulation. Together, these findings uncover CYFIP2 as a key regulatory link between axon-axon interactions, filopodial dynamics, and optic tract sorting. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins.

PubMed

Yalçın, Belgin; Zhao, Lu; Stofanko, Martin; O'Sullivan, Niamh C; Kang, Zi Han; Roost, Annika; Thomas, Matthew R; Zaessinger, Sophie; Blard, Olivier; Patto, Alex L; Sohail, Anood; Baena, Valentina; Terasaki, Mark; O'Kane, Cahir J

2017-07-25

Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

Interface Generation and Compositional Verification in JavaPathfinder

NASA Technical Reports Server (NTRS)

Giannakopoulou, Dimitra; Pasareanu, Corina

2009-01-01

We present a novel algorithm for interface generation of software components. Given a component, our algorithm uses learning techniques to compute a permissive interface representing legal usage of the component. Unlike our previous work, this algorithm does not require knowledge about the component s environment. Furthermore, in contrast to other related approaches, our algorithm computes permissive interfaces even in the presence of non-determinism in the component. Our algorithm is implemented in the JavaPathfinder model checking framework for UML statechart components. We have also added support for automated assume-guarantee style compositional verification in JavaPathfinder, using component interfaces. We report on the application of the presented approach to the generation of interfaces for flight software components.

Dust Wind Tails Around Rocks

NASA Technical Reports Server (NTRS)

1997-01-01

This image was taken by the Sojourner rover's left front camera on Sol 32. The Pathfinder lander is at right and is about 9 meters away. Wind tails of dust are clearly seen extending from the left side of many of the small rocks in the foreground. The large rocks on the horizon at left center are the next goal of Sojourner as it continues our exploration of Mars.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and managed the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech).

Review of the trajectory and atmospheric structure reconstruction for Mars Pathfinder

NASA Astrophysics Data System (ADS)

Withers, Paul; Towner, Martin; Hathi, Brijen; Zarnecki, John

2004-02-01

Mars Pathfinder landed on Mars on July 4, 1997. It used a novel deceleration procedure, consisting of a hypersonic aeroshell, a transonic parachute, retro-rockets, and airbags, to reach the surface safely. Its aerodynamic properties passively maintained a near-zero angle of attack throughout its entry. There were no gyroscopes to monitor attitude. Several different trajectory reconstructions have been based on the assumptions that accelerations along its symmetry axis are directed along its flight path and that accelerations in other directions are insignificant. The aerodynamics of Pathfinder once its parachute opened are still not well-understood and the available observations are probably not sufficient to improve matters significantly in the future.

James Webb Space Telescope Optical Telescope Element Integrated Science Instrument Module (OTIS) Status

NASA Technical Reports Server (NTRS)

Feinberg, Lee; Voyton, Mark; Lander, Julie; Keski-Kuha, Ritva; Matthews, Gary

2016-01-01

The James Webb Space Telescope Optical Telescope Element (OTE) and Integrated ScienceInstrument Module (ISIM)are integrated together to form the OTIS. Once integrated, the OTIS undergoes primary mirrorcenter of curvatureoptical tests, electrical and operational tests, acoustics and vibration testing at the Goddard SpaceFlight Center beforebeing shipped to the Johnson Space Center for cryogenic optical testing of the OTIS. In preparationfor the cryogenicoptical testing, the JWST project has built a Pathfinder telescope and has completed two OpticalGround SystemEquipment (OGSE) cryogenic optical tests with the Pathfinder. In this paper, we will summarize opticaltest results todate and status the final Pathfinder test and the OTIS integration and environmental test preparations

HOWARD EISEN, JPL'S LEAD MECHANICAL TECHNICIAN, HOLDS MARS PATHFINDER 'SOJOURNER' ROVER 1:1 SCALE DU

NASA Technical Reports Server (NTRS)

1996-01-01

The Mars Pathfinder 'Sojourner' rover l:l scale duplicate test vehicle is held by Howard Eisen, its lead mechanical technician from the Jet Propulsion Laboratory, with Kennedy Space Center's Vehicle Assembly Building looming in the background. The launch of NASA's Mars Pathfinder spacecraft aboard a McDonnell Douglas Delta II rocket is scheduled for Monday, Dec. 2, at 2:09:11 a.m. EST. This is a single instantaneous target launch time without a second opportunity on that day. Liftoff will occur from Pad B at Launch Complex 17 on Cape Canaveral Air Station, Fla. There is a 24-day launch opportunity which extends through Dec. 31.

LISA Pathfinder: A Mission Status

NASA Astrophysics Data System (ADS)

Hewitson, Martin; LISA Pathfinder Team Team

2016-03-01

On December 3rd at 04:04 UTC, The European Space Agency launched the LISA Pathfinder satellite on board a VEGA rocket from Kourou in French Guiana. After a series of orbit raising manoeuvres and a 2 month long transfer orbit, LISA Pathfinder arrived at L1. Following a period of commissioning, the science operations commenced at the start of March, beginning the demonstration of technologies and methodologies which pave the way for a future large-scale gravitational wave observatory in space. This talk will present the scientific goals of the mission, discuss the technologies being tested, elucidate the link to a future space-based observatory, such as LISA, and present preliminary results from the in-orbit operations and experiments.

Pathfinders: Making a Way from Segregation to Community Life.

ERIC Educational Resources Information Center

O'Brien, Connie Lyle; Mount, Beth; O'Brien, John; Rosen, Fredda

This paper describes the Pathfinders program in New York (New York), which works to facilitate the full integration of adults with developmental disabilities into workplaces and neighborhoods. The paper is organized around the question of whether students graduating from special education can find paid and volunteer work in community settings,…

AeroVironment's Jim Daley, Rik Meininger, Derek Lisoski and Wyatt Sadler (clockwise from bottom left) closely monitor systems testing of the Pathfinder-Plus.

NASA Image and Video Library

2004-09-17

AeroVironment's test director Jim Daley, backup pilot Rik Meininger, stability and controls engineer Derek Lisoski and pilot Wyatt Sadler (clockwise from bottom left) closely monitor systems testing of the Pathfinder-Plus solar aircraft from the control station.

Do Integrated Children's Services Improve Children's Outcomes?: Evidence from England's Children's Trust Pathfinders

ERIC Educational Resources Information Center

O'Brien, Margaret; Bachmann, Max O.; Jones, Natalia R.; Reading, Richard; Thoburn, June; Husbands, Chris; Shreeve, Ann; Watson, Jacqueline

2009-01-01

Thirty-five children's trust pathfinders, local cross-sector partnerships, were introduced across England in 2003 to promote greater integration in children's services. Using administrative performance data, this paper tracks yearly trends in child service outputs and child well-being outcomes from 1997 to 2004 in these local areas, including the…

Global Climate Change Pathfinder: A Guide to Information Resources. Second Edition.

ERIC Educational Resources Information Center

Pintozzi, Chestalene; Jones, Douglas E.

This pathfinder is a guide to scientific and technical aspects of global climate change including meteorological and climatological aspects; biological, agricultural, and public policy implications; and the chemical processes involved. Sources are arranged by type of publication and include: (1) 10 reference sources; (2) 12 bibliographies; (3) 44…

Pathfinder. Volume 8, Number 3, May/June 2010. Technology - Rendering an Ever-Clearer Picture

DTIC Science & Technology

2010-06-01

Agency,Office of Corporate Communications,4600 Sangamore Road, Mail Stop D-54,Bethesda,MD, 20816 -5003 8. PERFORMING ORGANIZATION REPORT NUMBER 9...Bethesda, MD 20816 -5003 Telephone: (301) 227-7388, DSN 287-7388 E-mail: pathfinder@nga.mil Director Vice Adm. Robert B. Murrett, U.S. Navy Deputy

Wind Drifts at Viking 1 Landing Site

NASA Technical Reports Server (NTRS)

1997-01-01

This image is of so-called wind drifts seen at the Viking 1 landing site. These are somewhat different from the features seen at the Pathfinder site in two important ways. 1) These landforms have no apparent slip-or avalanche-face as do both terrestrial dunes and the Pathfinder features, and may represent deposits of sediment falling from the air, as opposed to dune sand, which 'hops' or saltates along the ground; 2) these features may indicate erosion on one side, because of the layering and apparent scouring on their right sides. They may, therefore have been deposited by a wind moving left to right, partly or weakly cemented or solidified by surface processes at some later time, then eroded by a second wind (right to left), exposing their internal structure.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech).

Statistical analysis of soil geochemical data to identify pathfinders associated with mineral deposits: An example from the Coles Hill uranium deposit, Virginia, USA

USGS Publications Warehouse

Levitan, Denise M.; Zipper, Carl E.; Donovan, Patricia; Schreiber, Madeline E.; Seal, Robert; Engle, Mark A.; Chermak, John A.; Bodnar, Robert J.; Johnson, Daniel K.; Aylor, Joseph G.

2015-01-01

Soil geochemical anomalies can be used to identify pathfinders in exploration for ore deposits. In this study, compositional data analysis is used with multivariate statistical methods to analyse soil geochemical data collected from the Coles Hill uranium deposit, Virginia, USA, to identify pathfinders associated with this deposit. Elemental compositions and relationships were compared between the collected Coles Hill soil and reference soil samples extracted from a regional subset of a national-scale geochemical survey. Results show that pathfinders for the Coles Hill deposit include light rare earth elements (La and Ce), which, when normalised by their Al content, are correlated with U/Al, and elevated Th/Al values, which are not correlated with U/Al, supporting decoupling of U from Th during soil generation. These results can be used in genetic and weathering models of the Coles Hill deposit, and can also be applied to future prospecting for similar U deposits in the eastern United States, and in regions with similar geological/climatic conditions.

MARS PATHFINDER CAMERA TEST IN SAEF-2

NASA Technical Reports Server (NTRS)

1996-01-01

Jet Propulsion Laboratory (JPL) workers conduct a systems test of the Mars Pathfinder imager, installed atop the Pathfinder lander (with JPL insignia). The imager is the white cyclindrical structure close to the worker's gloved hand. At left is the small rover that will be deployed from the lander to explore the Martian surface. The rover is mounted on one of three petals that will be attached to the lander. The two-pronged mast extending upward from the lander is for the low-gain antenna. The imager is mounted on a mast that will be extended after the lander touches down on Mars, affording a better view of the area. The imager is a camera that will transmit images of the Martian surface as well as the trail left by the rover, helping researchers to better understand the composition of the soil. It also is equipped with selectable filters for gathering data about the atmosphere of the Red Planet. JPL manages the Mars Pathfinder project for NASA. The journey to Mars is scheduled to begin with liftoff Dec. 2 aboard a Delta II expendable launch vehicle.

Actuation crosstalk in free-falling systems: Torsion pendulum results for the engineering model of the LISA pathfinder gravitational reference sensor

NASA Astrophysics Data System (ADS)

Bassan, M.; Cavalleri, A.; De Laurentis, M.; De Marchi, F.; De Rosa, R.; Di Fiore, L.; Dolesi, R.; Finetti, N.; Garufi, F.; Grado, A.; Hueller, M.; Marconi, L.; Milano, L.; Minenkov, Y.; Pucacco, G.; Stanga, R.; Vetrugno, D.; Visco, M.; Vitale, S.; Weber, W. J.

2018-01-01

In this paper we report on measurements on actuation crosstalk, relevant to the gravitational reference sensors for LISA Pathfinder and LISA. In these sensors, a Test Mass (TM) falls freely within a system of electrodes used for readout and control. These measurements were carried out on ground with a double torsion pendulum that allowed us to estimate both the torque injected into the sensor when a control force is applied and, conversely, the force leaking into the translational degree of freedom due to the applied torque.The values measured on our apparatus (the engineering model of the LISA Pathfinder sensor) agree to within 0.2% (over a maximum measured crosstalk of 1%) with predictions of a mathematical model when measuring force to torque crosstalk, while it is somewhat larger than expected (up to 3.5%) when measuring torque to force crosstalk. However, the values in the relevant range, i.e. when the TM is well centered ( ± 10 μm) in the sensor, remain smaller than 0.2%, satisfying the LISA Pathfinder requirements.

ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm.

PubMed

Yahyavi, Mani; Abouzeid, Hana; Gawdat, Ghada; de Preux, Anne-Sophie; Xiao, Tong; Bardakjian, Tanya; Schneider, Adele; Choi, Alex; Jorgenson, Eric; Baier, Herwig; El Sada, Mohamad; Schorderet, Daniel F; Slavotinek, Anne M

2013-08-15

The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems.

ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm

PubMed Central

Yahyavi, Mani; Abouzeid, Hana; Gawdat, Ghada; de Preux, Anne-Sophie; Xiao, Tong; Bardakjian, Tanya; Schneider, Adele; Choi, Alex; Jorgenson, Eric; Baier, Herwig; El Sada, Mohamad; Schorderet, Daniel F.; Slavotinek, Anne M.

2013-01-01

The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew–Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems. PMID:23591992

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome.

PubMed

Fung, Lawrence K; Quintin, Eve-Marie; Haas, Brian W; Reiss, Allan L

2012-04-01

The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well - microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.

GSK-3 mediates the okadaic acid-induced modification of collapsin response mediator protein-2 in human SK-N-SH neuroblastoma cells.

PubMed

Ni, Mei-Hui; Wu, Chih-Ching; Chan, Wen-Hsiung; Chien, Kun-Yi; Yu, Jau-Song

2008-04-15

Collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in axonal outgrowth and microtubule dynamics, is aberrantly phosphorylated in Alzheimer's disease (AD) brain. Alteration of glycogen synthase kinase-3 (GSK-3) activity is associated with the pathogenesis of AD. Here, we show that CRMP-2 is one of the major substrates for GSK-3 in pig brain extracts. Both GSK-3alpha and 3beta phosphorylate purified pig brain CRMP-2 and significantly alter its mobility in SDS-gels, resembling the CRMP-2 modification observed in AD brain. Interestingly, this modification can be detected in SK-N-SH neuroblastoma cells treated with a phosphatase inhibitor, okadaic acid (OA), and GSK-3 inhibitors completely block this OA-induced event. Knockdown of both GSK-3alpha and 3beta, but not either kinase alone, impairs OA-induced modification of CRMP-2. Mutation of Ser-518 or Ser-522 of CRMP-2, which are highly phosphorylated in AD brain, to Ala blocks the OA-induced modification of CRMP-2 in SK-N-SH cells. Ser-522 prephosphorylated by Cdk5 is required for subsequent GSK-3alpha-mediated phosphorylation of CRMP-2 in vitro. Collectively, our results demonstrate for the first time that OA can induce phosphorylation of CRMP-2 in SK-N-SH cells at sites aberrantly phosphorylated in AD brain, and both GSK-3alpha and 3beta and Ser-522 kinase(s) are involved in this process.

Recurrent 15q11.2 BP1-BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders.

PubMed

Picinelli, Chiara; Lintas, Carla; Piras, Ignazio Stefano; Gabriele, Stefano; Sacco, Roberto; Brogna, Claudia; Persico, Antonio Maria

2016-12-01

Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg 2+ levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

PubMed Central

Chisholm, Andrew D.; Hutter, Harald; Jin, Yishi; Wadsworth, William G.

2016-01-01

The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made in understanding the molecular basis of axon outgrowth and guidance. Genetic analysis in Caenorhabditis elegans has played a key role in elucidating conserved pathways regulating axon guidance, including Netrin signaling, the slit Slit/Robo pathway, Wnt signaling, and others. Axon guidance factors were first identified by screens for mutations affecting animal behavior, and by direct visual screens for axon guidance defects. Genetic analysis of these pathways has revealed the complex and combinatorial nature of guidance cues, and has delineated how cues guide growth cones via receptor activity and cytoskeletal rearrangement. Several axon guidance pathways also affect directed migrations of non-neuronal cells in C. elegans, with implications for normal and pathological cell migrations in situations such as tumor metastasis. The small number of neurons and highly stereotyped axonal architecture of the C. elegans nervous system allow analysis of axon guidance at the level of single identified axons, and permit in vivo tests of prevailing models of axon guidance. C. elegans axons also have a robust capacity to undergo regenerative regrowth after precise laser injury (axotomy). Although such axon regrowth shares some similarities with developmental axon outgrowth, screens for regrowth mutants have revealed regeneration-specific pathways and factors that were not identified in developmental screens. Several areas remain poorly understood, including how major axon tracts are formed in the embryo, and the function of axon regeneration in the natural environment. PMID:28114100

Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

PubMed Central

Franssen, Elske H. P.; Zhao, Rong-Rong; Koseki, Hiroaki; Kanamarlapudi, Venkateswarlu; Hoogenraad, Casper C.

2015-01-01

Integrins are adhesion and survival molecules involved in axon growth during CNS development, as well as axon regeneration after injury in the peripheral nervous system (PNS). Adult CNS axons do not regenerate after injury, partly due to a low intrinsic growth capacity. We have previously studied the role of integrins in axon growth in PNS axons; in the present study, we investigate whether integrin mechanisms involved in PNS regeneration may be altered or lacking from mature CNS axons by studying maturing CNS neurons in vitro. In rat cortical neurons, we find that integrins are present in axons during initial growth but later become restricted to the somato-dendritic domain. We investigated how this occurs and whether it can be altered to enhance axonal growth potential. We find a developmental change in integrin trafficking; transport becomes predominantly retrograde throughout axons, but not dendrites, as neurons mature. The directionality of transport is controlled through the activation state of ARF6, with developmental upregulation of the ARF6 GEF ARNO enhancing retrograde transport. Lowering ARF6 activity in mature neurons restores anterograde integrin flow, allows transport into axons, and increases axon growth. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational modifications of tubulin with taxol also allows integrins into the proximal axon. The experiments suggest that the developmental loss of regenerative ability in CNS axons is due to exclusion of growth-related molecules due to changes in trafficking. PMID:26019348

Relating MBSE to Spacecraft Development: A NASA Pathfinder

NASA Technical Reports Server (NTRS)

Othon, Bill

2016-01-01

The NASA Engineering and Safety Center (NESC) has sponsored a Pathfinder Study to investigate how Model Based Systems Engineering (MBSE) and Model Based Engineering (MBE) techniques can be applied by NASA spacecraft development projects. The objectives of this Pathfinder Study included analyzing both the products of the modeling activity, as well as the process and tool chain through which the spacecraft design activities are executed. Several aspects of MBSE methodology and process were explored. Adoption and consistent use of the MBSE methodology within an existing development environment can be difficult. The Pathfinder Team evaluated the possibility that an "MBSE Template" could be developed as both a teaching tool as well as a baseline from which future NASA projects could leverage. Elements of this template include spacecraft system component libraries, data dictionaries and ontology specifications, as well as software services that do work on the models themselves. The Pathfinder Study also evaluated the tool chain aspects of development. Two chains were considered: 1. The Development tool chain, through which SysML model development was performed and controlled, and 2. The Analysis tool chain, through which both static and dynamic system analysis is performed. Of particular interest was the ability to exchange data between SysML and other engineering tools such as CAD and Dynamic Simulation tools. For this study, the team selected a Mars Lander vehicle as the element to be designed. The paper will discuss what system models were developed, how data was captured and exchanged, and what analyses were conducted.

A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders

PubMed Central

Reinhard, Sarah M.; Razak, Khaleel; Ethell, Iryna M.

2015-01-01

The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called ‘critical periods.’ MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer’s disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders. PMID:26283917

L1CAM/Neuroglian controls the axon-axon interactions establishing layered and lobular mushroom body architecture.

PubMed

Siegenthaler, Dominique; Enneking, Eva-Maria; Moreno, Eliza; Pielage, Jan

2015-03-30

The establishment of neuronal circuits depends on the guidance of axons both along and in between axonal populations of different identity; however, the molecular principles controlling axon-axon interactions in vivo remain largely elusive. We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory. We addressed the regulatory mechanisms controlling homophilic Neuroglian-mediated cell adhesion by analyzing targeted mutations of extra- and intracellular Neuroglian domains in combination with cell type-specific rescue assays in vivo. We demonstrate independent and cooperative domain requirements: intercalating growth depends on homophilic adhesion mediated by extracellular Ig domains. For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations. Together, our results provide novel mechanistic insights into cell adhesion molecule-mediated axon-axon interactions that enable precise assembly of complex neuronal circuits. © 2015 Siegenthaler et al.

O-GlcNAc Transferase Is Essential for Sensory Neuron Survival and Maintenance

PubMed Central

Su, Cathy

2017-01-01

O-GlcNAc transferase (OGT) regulates a wide range of cellular processes through the addition of the O-GlcNAc sugar moiety to thousands of protein substrates. Because nutrient availability affects the activity of OGT, its role has been broadly studied in metabolic tissues. OGT is enriched in the nervous system, but little is known about its importance in basic neuronal processes in vivo. Here, we show that OGT is essential for sensory neuron survival and maintenance in mice. Sensory neuron-specific knock-out of OGT results in behavioral hyposensitivity to thermal and mechanical stimuli accompanied by decreased epidermal innervation and cell-body loss in the dorsal root ganglia. These effects are observed early in postnatal development and progress as animals age. Cultured sensory neurons lacking OGT also exhibit decreased axonal outgrowth. The effects on neuronal health in vivo are not solely due to disruption of developmental processes, because inducing OGT knock-out in the sensory neurons of adult mice results in a similar decrease in nerve fiber endings and cell bodies. Significant nerve-ending loss occurs before a decrease in cell bodies; this phenotype is indicative of axonal dieback that progresses to neuronal death. Our findings demonstrate that OGT is important in regulating axonal maintenance in the periphery and the overall health and survival of sensory neurons. SIGNIFICANCE STATEMENT We show the importance of O-GlcNAc transferase (OGT) for sensory neuron health and survival in vivo. This study is the first to find that loss of OGT results in neuronal cell death. Moreover, it suggests that aberrant O-GlcNAc signaling can contribute to the development of neuropathy. The sensory neurons lie outside of the blood–brain barrier and therefore, compared to central neurons, may have a greater need for mechanisms of metabolic sensing and compensation. Peripheral sensory neurons in particular are subject to degeneration in diabetes. Our findings provide a foundation for understanding the role of OGT under normal physiological conditions in the peripheral nervous system. This knowledge will be important for gaining greater insight into such disease states as diabetic neuropathy. PMID:28115479

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes

PubMed Central

Smith, Darrell R.; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A.; Fernyhough, Paul

2012-01-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3–5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway. PMID:22561641

NASA's Webb "Pathfinder Telescope" Successfully Completes First Super-Cold Optical Test

NASA Image and Video Library

2017-12-08

Testing is crucial part of NASA's success on Earth and in space. So, as the actual flight components of NASA's James Webb Space Telescope come together, engineers are testing the non-flight equipment to ensure that tests on the real Webb telescope later goes safely and according to plan. Recently, the "pathfinder telescope," or just “Pathfinder,” completed its first super-cold optical test that resulted in many first-of-a-kind demonstrations. "This test is the first dry-run of the equipment and procedures we will use to conduct an end-to-end optical test of the flight telescope and instruments," said Mark Clampin, Webb telescope Observatory Project Scientist at NASA's Goddard Space Flight Center in Greenbelt, Maryland. "It provides confidence that once the flight telescope is ready, we are fully prepared for a successful test of the flight hardware." The Pathfinder is a non-flight replica of the Webb telescope’s center section backplane, or “backbone,” that includes mirrors. The flight backplane comes in three segments, a center section and two wing-like parts, all of which will support large hexagonal mirrors on the Webb telescope. The pathfinder only consists of the center part of the backplane. However, during the test, it held two full size spare primary mirror segments and a full size spare secondary mirror to demonstrate the ability to optically test and align the telescope at the planned operating temperatures of -400 degrees Fahrenheit (-240 Celsius). Read more: www.nasa.gov/feature/goddard/nasas-webb-pathfinder-telesc... Credit: NASA/Goddard/Chris Gunn NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

An ex vivo laser-induced spinal cord injury model to assess mechanisms of axonal degeneration in real-time.

PubMed

Okada, Starlyn L M; Stivers, Nicole S; Stys, Peter K; Stirling, David P

2014-11-25

Injured CNS axons fail to regenerate and often retract away from the injury site. Axons spared from the initial injury may later undergo secondary axonal degeneration. Lack of growth cone formation, regeneration, and loss of additional myelinated axonal projections within the spinal cord greatly limits neurological recovery following injury. To assess how central myelinated axons of the spinal cord respond to injury, we developed an ex vivo living spinal cord model utilizing transgenic mice that express yellow fluorescent protein in axons and a focal and highly reproducible laser-induced spinal cord injury to document the fate of axons and myelin (lipophilic fluorescent dye Nile Red) over time using two-photon excitation time-lapse microscopy. Dynamic processes such as acute axonal injury, axonal retraction, and myelin degeneration are best studied in real-time. However, the non-focal nature of contusion-based injuries and movement artifacts encountered during in vivo spinal cord imaging make differentiating primary and secondary axonal injury responses using high resolution microscopy challenging. The ex vivo spinal cord model described here mimics several aspects of clinically relevant contusion/compression-induced axonal pathologies including axonal swelling, spheroid formation, axonal transection, and peri-axonal swelling providing a useful model to study these dynamic processes in real-time. Major advantages of this model are excellent spatiotemporal resolution that allows differentiation between the primary insult that directly injures axons and secondary injury mechanisms; controlled infusion of reagents directly to the perfusate bathing the cord; precise alterations of the environmental milieu (e.g., calcium, sodium ions, known contributors to axonal injury, but near impossible to manipulate in vivo); and murine models also offer an advantage as they provide an opportunity to visualize and manipulate genetically identified cell populations and subcellular structures. Here, we describe how to isolate and image the living spinal cord from mice to capture dynamics of acute axonal injury.

Thromboembolism and congenital malformations: from Duane syndrome to thalidomide embryopathy.

PubMed

Parsa, Cameron F; Robert, Matthieu P

2013-04-01

To propose a pathophysiologic mechanism to unify a variety of disparate sporadic congenital malformations. Inductive and deductive analyses to correlate malformation laterality with asymmetries in thoracic anatomy, critical analysis of malformations with female predominance, and concepts of hydrodynamic pressure gradients in vascular growth were applied to the ensuing development of guiding tissue scaffolds for cellular proliferation, differentiation, and apoptosis. Duane syndrome may develop following a focal vascular insult to the sixth nerve trunk with axonal degeneration, allowing for substitutive innervation from third nerve axons to the lateral rectus muscle. Causative fibrin clots may originate from the venous system and paradoxically migrate through physiological right-to left shunts, or they may arise directly from the heart. Hence, the unilateral, left-sided, and female predominance of Duane syndrome results from the asymmetry in the thoracic anatomy and from thrombosis risk factors. Embolic occlusions may also alter local hemodynamic pressure gradients, leading to the compensatory enlargement and persistence of the fetal vasculature and may dysregulate tissue growth. Within the eye, this results in forms of Peters anomaly, unilateral congenital cataracts, and the morning glory disc anomaly, all in the vascular territory of the carotid arteries that also share a propensity for left-sided involvement in girls. Most aberrant misinnervation phenomena (eg, jaw-winking syndrome, crocodile tear syndrome, Brown syndrome, and congenital fibrosis syndrome) and, by extrapolation, the hypoplasia or dysgenesis of noncephalic anatomical structures (including limbs) may be similarly explained. Such malformations will occur more frequently under thrombogenic conditions, such as those induced by thalidomide. Fibrin emboli and focal hypoperfusion may explain the development of many sporadic congenital malformations.

Assessment of Mars Pathfinder landing site predictions

USGS Publications Warehouse

Golombek, M.P.; Moore, H.J.; Haldemann, A.F.C.; Parker, T.J.; Schofield, J.T.

1999-01-01

Remote sensing data at scales of kilometers and an Earth analog were used to accurately predict the characteristics of the Mars Pathfinder landing site at a scale of meters. The surface surrounding the Mars Pathfinder lander in Ares Vallis appears consistent with orbital interpretations, namely, that it would be a rocky plain composed of materials deposited by catastrophic floods. The surface and observed maximum clast size appears similar to predictions based on an analogous surface of the Ephrata Fan in the Channeled Scabland of Washington state. The elevation of the site measured by relatively small footprint delay-Doppler radar is within 100 m of that determined by two-way ranging and Doppler tracking of the spacecraft. The nearly equal elevations of the Mars Pathfinder and Viking Lander 1 sites allowed a prediction of the atmospheric conditions with altitude (pressure, temperature, and winds) that were well within the entry, descent, and landing design margins. High-resolution (~38 m/pixel) Viking Orbiter 1 images showed a sparsely cratered surface with small knobs with relatively low slopes, consistent with observations of these features from the lander. Measured rock abundance is within 10% of that expected from Viking orbiter thermal observations and models. The fractional area covered by large, potentially hazardous rocks observed is similar to that estimated from model rock distributions based on data from the Viking landing sites, Earth analog sites, and total rock abundance. The bulk and fine-component thermal inertias measured from orbit are similar to those calculated from the observed rock size-frequency distribution. A simple radar echo model based on the reflectivity of the soil (estimated from its bulk density), and the measured fraction of area covered by rocks was used to approximate the quasi-specular and diffuse components of the Earth-based radar echos. Color and albedo orbiter data were used to predict the relatively dust free or unweathered surface around the Pathfinder lander compared to the Viking landing sites. Comparisons with the experiences of selecting the Viking landing sites demonstrate the enormous benefit the Viking data and its analyses and models had on the successful predictions of the Pathfinder site. The Pathfinder experience demonstrates that, in certain locations, geologic processes observed in orbiter data can be used to infer surface characteristics where those processes dominate over other processes affecting the Martian surface layer. Copyright 1999 by the American Geophysical Union.

Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

PubMed Central

Yalçın, Belgin; Zhao, Lu; Stofanko, Martin; O'Sullivan, Niamh C; Kang, Zi Han; Roost, Annika; Thomas, Matthew R; Zaessinger, Sophie; Blard, Olivier; Patto, Alex L; Sohail, Anood; Baena, Valentina; Terasaki, Mark; O'Kane, Cahir J

2017-01-01

Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function. DOI: http://dx.doi.org/10.7554/eLife.23882.001 PMID:28742022

Evidence That Descending Cortical Axons Are Essential for Thalamocortical Axons to Cross the Pallial-Subpallial Boundary in the Embryonic Forebrain

PubMed Central

Chen, Yijing; Magnani, Dario; Theil, Thomas; Pratt, Thomas; Price, David J.

2012-01-01

Developing thalamocortical axons traverse the subpallium to reach the cortex located in the pallium. We tested the hypothesis that descending corticofugal axons are important for guiding thalamocortical axons across the pallial-subpallial boundary, using conditional mutagenesis to assess the effects of blocking corticofugal axonal development without disrupting thalamus, subpallium or the pallial-subpallial boundary. We found that thalamic axons still traversed the subpallium in topographic order but did not cross the pallial-subpallial boundary. Co-culture experiments indicated that the inability of thalamic axons to cross the boundary was not explained by mutant cortex developing a long-range chemorepulsive action on thalamic axons. On the contrary, cortex from conditional mutants retained its thalamic axonal growth-promoting activity and continued to express Nrg-1, which is responsible for this stimulatory effect. When mutant cortex was replaced with control cortex, corticofugal efferents were restored and thalamic axons from conditional mutants associated with them and crossed the pallial-subpallial boundary. Our study provides the most compelling evidence to date that cortical efferents are required to guide thalamocortical axons across the pallial-subpallial boundary, which is otherwise hostile to thalamic axons. These results support the hypothesis that thalamic axons grow from subpallium to cortex guided by cortical efferents, with stimulation from diffusible cortical growth-promoting factors. PMID:22412988

Retrograde and Wallerian Axonal Degeneration Occur Synchronously after Retinal Ganglion Cell Axotomy

PubMed Central

Kanamori, Akiyasu; Catrinescu, Maria-Magdalena; Belisle, Jonathan M.; Costantino, Santiago; Levin, Leonard A.

2013-01-01

Axonal injury and degeneration are pivotal pathological events in diseases of the nervous system. In the past decade, it has been recognized that the process of axonal degeneration is distinct from somal degeneration and that axoprotective strategies may be distinct from those that protect the soma. Preserving the cell body via neuroprotection cannot improve function if the axon is damaged, because the soma is still disconnected from its target. Therefore, understanding the mechanisms of axonal degeneration is critical for developing new therapeutic interventions for axonal disease treatment. We combined in vivo imaging with a multilaser confocal scanning laser ophthalmoscope and in vivo axotomy with a diode-pumped solid-state laser to assess the time course of Wallerian and retrograde degeneration of unmyelinated retinal ganglion cell axons in living rats for 4 weeks after intraretinal axotomy. Laser injury resulted in reproducible axon loss both distal and proximal to the site of injury. Longitudinal polarization-sensitive imaging of axons demonstrated that Wallerian and retrograde degeneration occurred synchronously. Neurofilament immunostaining of retinal whole-mounts confirmed axonal loss and demonstrated sparing of adjacent axons to the axotomy site. In vivo fluorescent imaging of axonal transport and photobleaching of labeled axons demonstrated that the laser axotomy model did not affect adjacent axon function. These results are consistent with a shared mechanism for Wallerian and retrograde degeneration. PMID:22642911

Altered impulse activity modifies synaptic physiology and mitochondria in crayfish phasic motor neurons.

PubMed

Nguyen, P V; Atwood, H L

1994-12-01

1. Crayfish phasic motor synapses produce large initial excitatory postsynaptic potentials (EPSPs) that fatigue rapidly during high-frequency stimulation. Periodic in vivo stimulation of an identified phasic abdominal extensor motor neuron (axon 3) induced long-term adaptation (LTA) of neuromuscular transmission: initial EPSP amplitude became smaller and synaptic depression was significantly reduced. We tested the hypothesis that activity-induced synaptic fatigue-resistance seen during LTA was dependent upon, or correlated with, mitochondrial oxidative competence. 2. Periodic unilateral conditioning stimulation of axon 3 entering each of two adjacent homologous abdominal segments (segments 2 and 3) increased the synaptic stamina in both "conditioned" axons; mean final EPSP amplitudes, recorded after 20 min of 5-Hz test stimulation, were significantly larger than those measured with the same protocol from contralateral unstimulated axons. 3. During 5-Hz test stimulation of the conditioned axon 3 of segment 3, acute superfusion with 0.8 mM dinitrophenol or 20 mM sodium azide [inhibitors of oxidative adenosinetriphosphate (ATP) synthesis] produced increased synaptic depression. Drug-free saline superfusion of the conditioned axon 3 of segment 2 in these same animals did not affect the increased synaptic fatigue resistance seen in this segment. Thus both successful induction (in axon 3 of saline-perfused segment 2) and attenuation (in axon 3 of drug-perfused segment 3) of the increased synaptic stamina can be demonstrated with this twin-segment conditioning protocol. 4. Confocal microscopic imaging of mitochondrial rhodamine-123 (Rh123) fluorescence was used to assess relative oxidative competence of conditioned and unconditioned phasic axons. Conditioned phasic axons showed significantly higher mean mitochondrial Rh123 fluorescence than contralateral unstimulated axons. In the same preparations that showed increased postconditioning Rh123 fluorescence, the synaptic fatigue resistance measured from conditioned axon 3 was also significantly greater than that recorded from contralateral unstimulated axon 3. 5. Axotomy of the phasic extensor nerve root (containing axon 3), before in vivo conditioning stimulation of its decentralized segment, prevented induction of both the increased synaptic stamina in axon 3 and the enhanced mitochondrial fluorescence in decentralized motor axons of the nerve root. Hence, induction of both changes requires axonal transport of materials between the soma and the motor synapses of axon 3. 5. Axotomy of the phasic extensor nerve root (containing axon 3), before in vivo conditioning stimulation of its decentralized segment, Prevented induction of both the increased synaptic stamina in axon 3 and the enhanced mitochondrial fluorescence in decentralized motor axons of the nerve root Hence, induction of both changes requires axonal transport of materials between the soma and the motor synapses of axon 3 6. Because mitochondrial Rh123 fluorescence is primarily dependent upon the oxidative activity of these organelles, our findings suggest that conditioning stimulation of phasic extensor axon 3 increases its mitochondrial oxidative competence and that the enhanced synaptic stamina seen during LTA in axon 3 is correlated with, and dependent upon, oxidative activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Identified motor terminals in Drosophila larvae show distinct differences in morphology and physiology

NASA Technical Reports Server (NTRS)

Lnenicka, G. A.; Keshishian, H.

2000-01-01

In Drosophila, the type I motor terminals innervating the larval ventral longitudinal muscle fibers 6 and 7 have been the most popular preparation for combining synaptic studies with genetics. We have further characterized the normal morphological and physiological properties of these motor terminals and the influence of muscle size on terminal morphology. Using dye-injection and physiological techniques, we show that the two axons supplying these terminals have different innervation patterns: axon 1 innervates only muscle fibers 6 and 7, whereas axon 2 innervates all of the ventral longitudinal muscle fibers. This difference in innervation pattern allows the two axons to be reliably identified. The terminals formed by axons 1 and 2 on muscle fibers 6 and 7 have the same number of branches; however, axon 2 terminals are approximately 30% longer than axon 1 terminals, resulting in a corresponding greater number of boutons for axon 2. The axon 1 boutons are approximately 30% wider than the axon 2 boutons. The excitatory postsynaptic potential (EPSP) produced by axon 1 is generally smaller than that produced by axon 2, although the size distributions show considerable overlap. Consistent with vertebrate studies, there is a correlation between muscle fiber size and terminal size. For a single axon, terminal area and length, the number of terminal branches, and the number of boutons are all correlated with muscle fiber size, but bouton size is not. During prolonged repetitive stimulation, axon 2 motor terminals show synaptic depression, whereas axon 1 EPSPs facilitate. The response to repetitive stimulation appears to be similar at all motor terminals of an axon. Copyright 2000 John Wiley & Sons, Inc.

Physical Biology of Axonal Damage.

PubMed

de Rooij, Rijk; Kuhl, Ellen

2018-01-01

Excessive physical impacts to the head have direct implications on the structural integrity at the axonal level. Increasing evidence suggests that tau, an intrinsically disordered protein that stabilizes axonal microtubules, plays a critical role in the physical biology of axonal injury. However, the precise mechanisms of axonal damage remain incompletely understood. Here we propose a biophysical model of the axon to correlate the dynamic behavior of individual tau proteins under external physical forces to the evolution of axonal damage. To propagate damage across the scales, we adopt a consistent three-step strategy: First, we characterize the axonal response to external stretches and stretch rates for varying tau crosslink bond strengths using a discrete axonal damage model. Then, for each combination of stretch rates and bond strengths, we average the axonal force-stretch response of n = 10 discrete simulations, from which we derive and calibrate a homogenized constitutive model. Finally, we embed this homogenized model into a continuum axonal damage model of [1-d]-type in which d is a scalar damage parameter that is driven by the axonal stretch and stretch rate. We demonstrate that axonal damage emerges naturally from the interplay of physical forces and biological crosslinking. Our study reveals an emergent feature of the crosslink dynamics: With increasing loading rate, the axonal failure stretch increases, but axonal damage evolves earlier in time. For a wide range of physical stretch rates, from 0.1 to 10 /s, and biological bond strengths, from 1 to 100 pN, our model predicts a relatively narrow window of critical damage stretch thresholds, from 1.01 to 1.30, which agrees well with experimental observations. Our biophysical damage model can help explain the development and progression of axonal damage across the scales and will provide useful guidelines to identify critical damage level thresholds in response to excessive physical forces.

Myelinated sensory and alpha motor axon regeneration in peripheral nerve neuromas

NASA Technical Reports Server (NTRS)

Macias, M. Y.; Lehman, C. T.; Sanger, J. R.; Riley, D. A.

1998-01-01

Histochemical staining for carbonic anhydrase and cholinesterase (CE) activities was used to analyze sensory and motor axon regeneration, respectively, during neuroma formation in transected and tube-encapsulated peripheral nerves. Median-ulnar and sciatic nerves in the rodent model permitted testing whether a 4 cm greater distance of the motor neuron soma from axotomy site or intrinsic differences between motor and sensory neurons influenced regeneration and neuroma formation 10, 30, and 90 days later. Ventral root radiculotomy confirmed that CE-stained axons were 97% alpha motor axons. Distance significantly delayed axon regeneration. When distance was negligible, sensory axons grew out sooner than motor axons, but motor axons regenerated to a greater quantity. These results indicate regeneration differences between axon subtypes and suggest more extensive branching of motor axons within the neuroma. Thus, both distance from injury site to soma and inherent motor and sensory differences should be considered in peripheral nerve repair strategies.

Squid Giant Axon Contains Neurofilament Protein mRNA but does not Synthesize Neurofilament Proteins.

PubMed

Gainer, Harold; House, Shirley; Kim, Dong Sun; Chin, Hemin; Pant, Harish C

2017-04-01

When isolated squid giant axons are incubated in radioactive amino acids, abundant newly synthesized proteins are found in the axoplasm. These proteins are translated in the adaxonal Schwann cells and subsequently transferred into the giant axon. The question as to whether any de novo protein synthesis occurs in the giant axon itself is difficult to resolve because the small contribution of the proteins possibly synthesized intra-axonally is not easily distinguished from the large amounts of the proteins being supplied from the Schwann cells. In this paper, we reexamine this issue by studying the synthesis of endogenous neurofilament (NF) proteins in the axon. Our laboratory previously showed that NF mRNA and protein are present in the squid giant axon, but not in the surrounding adaxonal glia. Therefore, if the isolated squid axon could be shown to contain newly synthesized NF protein de novo, it could not arise from the adaxonal glia. The results of experiments in this paper show that abundant 3H-labeled NF protein is synthesized in the squid giant fiber lobe containing the giant axon's neuronal cell bodies, but despite the presence of NF mRNA in the giant axon no labeled NF protein is detected in the giant axon. This lends support to the glia-axon protein transfer hypothesis which posits that the squid giant axon obtains newly synthesized protein by Schwann cell transfer and not through intra-axonal protein synthesis, and further suggests that the NF mRNA in the axon is in a translationally repressed state.

Airbag Retraction

NASA Image and Video Library

1997-07-05

This image shows that the Mars Pathfinder airbags have been successfully retracted, allowing safe deployment of the rover ramps. The Sojourner rover, still in its deployed position, is at center image, and rocks are visible in the background. Mars Pathfinder landed successfully on the surface of Mars today at 10:07 a.m. PDT. http://photojournal.jpl.nasa.gov/catalog/PIA00617

Pathfinder: The Geospatial Intelligence Magazine Serving the Front Line, March/April 2009. Volume 7, Number 2

DTIC Science & Technology

2009-04-01

ADDRESS(ES) National Geospatial-Intelligence Agency,4600 Sangamore Rd Mail Stop D-54,Bethesda,MD, 20816 -5003 8. PERFORMING ORGANIZATION REPORT NUMBER 9...Bethesda, MD 20816 -5003 Telephone: (301) 227-7388, DSN 287-7388 E-mail: pathfinder@nga.mil Director Vice Adm. Robert B. Murrett, U.S. Navy Deputy

Global comparisons between the modified Pathfinder derived sea surface temperature and skin temperatures from the along-track scanning radiometer on board ERS-2: how close are we getting?

NASA Technical Reports Server (NTRS)

Vazquez, J.

2001-01-01

Sea Surface Temperatures (SST) as derived from the Pathfinder Sea Surface Temperature Data Set and the Along-Track Scanning Radiometer on-board the European Remote Sensing Satellite provide a unique opportunity for comparing two independent SST data sets.

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, contracted by Goodloe Transportation of Chicago, departs from NASA’s Kennedy Space Center in Florida, with two containers on railcars for transport to the Jay Jay railroad yard. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the Rotation, Processing and Surge Facility (RPSF). Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

James Webb Space Telescope Optical Telescope Element/Integrated Science Instrument Module (OTIS) Status

NASA Technical Reports Server (NTRS)

Feinberg, Lee; Voyton, Mark; Lander, Juli; Keski-Kuha, Ritva; Matthews, Gary

2016-01-01

The James Webb Space Telescope Optical Telescope Element (OTE) and Integrated Science Instrument Module (ISIM) are integrated together to form the OTIS. Once integrated, the OTIS undergoes primary mirror center of curvature optical tests, electrical and operational tests, acoustics and vibration testing at the Goddard Space Flight Center before being shipped to the Johnson Space Center for cryogenic optical testing of the OTIS. In preparation for the cryogenic optical testing, the JWST project has built a Pathfinder telescope and has completed two Optical Ground System Equipment (OGSE) cryogenic optical tests with the Pathfinder. In this paper, we will summarize optical test results to date and status the final Pathfinder test and the OTIS integration and environmental test preparations

New Insights into the Geology of the Mars Pathfinder Landing Site from Spectral and Morphologic Analysis of the 12-Color Superpan Panorama

NASA Technical Reports Server (NTRS)

Murchie, S.; Barnouin-Jha, O.; Barnouin-Jha, K.; Bishop, J.; Johnson, J.; McSween, H.; Morris, R.

2003-01-01

New analyses of rocks and soils at the Mars Pathfinder landing site have been completed using the full Imager for Mars Pathfinder (IMP) 12- color SuperPan panorama. These revise early conclusions that rocks at the landing site are a single lithology coated only by windblown dust. We conclude instead that there is also a second lithology in addition to the dominant gray rock, and that it is consistent with highlands material excavated from beneath a thin veneer of northern plains; that many rocks have cemented coatings that formed during an early, probably wetter climate; and that young rocks excavated after coating formation ceased are mainly breccias or conglomerates.

LISA Pathfinder Spacecraft Artist Concept

NASA Image and Video Library

2015-12-03

This artist's concept shows ESA's LISA Pathfinder spacecraft, which launched on Dec. 3, 2015, from Kourou, French Guiana, will help pave the way for a mission to detect gravitational waves. LISA Pathfinder, led by the European Space Agency (ESA), is designed to test technologies that could one day detect gravitational waves. Gravitational waves, predicted by Einstein's theory of general relativity, are ripples in spacetime produced by any accelerating body. But the waves are so weak that Earth- or space-based observatories would likely only be able to directly detect such signals coming from massive astronomical systems, such as binary black holes or exploding stars. Detecting gravitational waves would be an important piece in the puzzle of how our universe began. http://photojournal.jpl.nasa.gov/catalog/PIA20196

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, contracted by Goodloe Transportation of Chicago, departs from the Rotation, Processing and Surge Facility (RPSF) at NASA’s Kennedy Space Center in Florida, with two containers on railcars for transport to the NASA Jay Jay railroad yard. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the RPSF. Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

Axon Regeneration in C. elegans

PubMed Central

Hammarlund, Marc; Jin, Yishi

2014-01-01

Single axon transection by laser surgery has made C. elegans a new model for axon regeneration. Multiple conserved molecular signaling modules have been discovered through powerful genetic screening. in vivo imaging with single cell and axon resolution has revealed unprecedented cellular dynamics in regenerating axons. Information from C. elegans has greatly expanded our knowledge of the molecular and cellular mechanisms of axon regeneration. PMID:24794753

Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor.

PubMed

Ma, Yihe; Bayguinov, Peter O; Jackson, Meyer B

2017-01-01

The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.

The Endocrine Dyscrasia that Accompanies Menopause and Andropause Induces Aberrant Cell Cycle Signaling that Triggers Cell Cycle Reentry of Post-mitotic Neurons, Neurodysfunction, Neurodegeneration and Cognitive Disease

PubMed Central

Atwood, Craig S.; Bowen, Richard L.

2016-01-01

Sex hormones are the physiological factors that regulate neurogenesis during embryogenesis and continuing through adulthood. These hormones support the formation of brain structures such as dendritic spines, axons and synapses required for the capture of information (memories). Intriguingly, a recent animal study has demonstrated that induction of neurogenesis results in the loss of previously encoded memories in animals (e.g. infantile amnesia). In this connection, much evidence now indicates that Alzheimer’s disease (AD) also involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Since sex hormones control when and how neurons proliferate and differentiate, the endocrine dyscrasia that accompanies menopause and andropause is a key signaling event that impacts neurogenesis and the acquisition, processing, storage and recall of memories. Here we review the biochemical, epidemiological and clinical evidence that alterations in endocrine signaling with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle with neurite retraction that leads to neuron dysfunction and death. When the reproductive axis is in balance, luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the ratio of LH:sex steroids as driving aberrant mitotic events mediated by the upregulation of tumor necrosis factor, amyloid-β precursor protein processing towards the production of mitogenic Aβ, and the activation of Cdk5, a key regulator of cell cycle progression and tau phosphorylation (a cardinal feature of both neurogenesis and neurodegeneration). Cognitive studies also demonstrate the negative consequences of a high LH:sex steroid ratio on human cognitive performance. Prospective epidemiological and clinical evidence in humans supports lowering the ratio of circulating gonadotropins-GnRH to sex steroids in reducing the incidence of AD and halting cognitive decline. Together, these data support endocrine dyscrasia and the subsequent loss of cell cycle control as an important etiological event in the development of neurodegenerative diseases including AD, stroke and Parkinson’s disease. PMID:26188949

An αII Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration.

PubMed

Huang, Claire Yu-Mei; Zhang, Chuansheng; Zollinger, Daniel R; Leterrier, Christophe; Rasband, Matthew N

2017-11-22

Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization. Avil-cre;Sptan1 f/f mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K + channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably, Avil-cre;Sptan1 f/f mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier. SIGNIFICANCE STATEMENT A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in maintenance of axon integrity. We demonstrate the role of the periodic spectrin-dependent cytoskeleton in axons and show that loss of αII spectrin from PNS axons causes preferential degeneration of large-diameter myelinated axons. We show that nodal αII spectrin is found at greater densities in large-diameter myelinated axons, suggesting that nodes are particularly vulnerable domains requiring a specialized cytoskeleton to protect against axon degeneration. Copyright © 2017 the authors 0270-6474/17/3711323-12$15.00/0.

Axon tension regulates fasciculation/defasciculation through the control of axon shaft zippering

PubMed Central

Šmít, Daniel; Fouquet, Coralie; Pincet, Frédéric; Zapotocky, Martin; Trembleau, Alain

2017-01-01

While axon fasciculation plays a key role in the development of neural networks, very little is known about its dynamics and the underlying biophysical mechanisms. In a model system composed of neurons grown ex vivo from explants of embryonic mouse olfactory epithelia, we observed that axons dynamically interact with each other through their shafts, leading to zippering and unzippering behavior that regulates their fasciculation. Taking advantage of this new preparation suitable for studying such interactions, we carried out a detailed biophysical analysis of zippering, occurring either spontaneously or induced by micromanipulations and pharmacological treatments. We show that zippering arises from the competition of axon-axon adhesion and mechanical tension in the axons, and provide the first quantification of the force of axon-axon adhesion. Furthermore, we introduce a biophysical model of the zippering dynamics, and we quantitatively relate the individual zipper properties to global characteristics of the developing axon network. Our study uncovers a new role of mechanical tension in neural development: the regulation of axon fasciculation. DOI: http://dx.doi.org/10.7554/eLife.19907.001 PMID:28422009

GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway.

PubMed

Guo, Xinzheng; Snider, William D; Chen, Bo

2016-03-14

Axons fail to regenerate after central nervous system (CNS) injury. Modulation of the PTEN/mTORC1 pathway in retinal ganglion cells (RGCs) promotes axon regeneration after optic nerve injury. Here, we report that AKT activation, downstream of Pten deletion, promotes axon regeneration and RGC survival. We further demonstrate that GSK3β plays an indispensable role in mediating AKT-induced axon regeneration. Deletion or inactivation of GSK3β promotes axon regeneration independently of the mTORC1 pathway, whereas constitutive activation of GSK3β reduces AKT-induced axon regeneration. Importantly, we have identified eIF2Bε as a novel downstream effector of GSK3β in regulating axon regeneration. Inactivation of eIF2Bε reduces both GSK3β and AKT-mediated effects on axon regeneration. Constitutive activation of eIF2Bε is sufficient to promote axon regeneration. Our results reveal a key role of the AKT-GSK3β-eIF2Bε signaling module in regulating axon regeneration in the adult mammalian CNS.

Glia to axon RNA transfer.

PubMed

Sotelo, José Roberto; Canclini, Lucía; Kun, Alejandra; Sotelo-Silveira, José Roberto; Calliari, Aldo; Cal, Karina; Bresque, Mariana; Dipaolo, Andrés; Farias, Joaquina; Mercer, John A

2014-03-01

The existence of RNA in axons has been a matter of dispute for decades. Evidence for RNA and ribosomes has now accumulated to a point at which it is difficult to question, much of the disputes turned to the origin of these axonal RNAs. In this review, we focus on studies addressing the origin of axonal RNAs and ribosomes. The neuronal soma as the source of most axonal RNAs has been demonstrated and is indisputable. However, the surrounding glial cells may be a supplemental source of axonal RNAs, a matter scarcely investigated in the literature. Here, we review the few papers that have demonstrated that glial-to-axon RNA transfer is not only feasible, but likely. We describe this process in both invertebrate axons and vertebrate axons. Schwann cell to axon ribosomes transfer was conclusively demonstrated (Court et al. [2008]: J. Neurosci 28:11024-11029; Court et al. [2011]: Glia 59:1529-1539). However, mRNA transfer still remains to be demonstrated in a conclusive way. The intercellular transport of mRNA has interesting implications, particularly with respect to the integration of glial and axonal function. This evolving field is likely to impact our understanding of the cell biology of the axon in both normal and pathological conditions. Most importantly, if the synthesis of proteins in the axon can be controlled by interacting glia, the possibilities for clinical interventions in injury and neurodegeneration are greatly increased. Copyright © 2013 Wiley Periodicals, Inc.

Axonal transport: cargo-specific mechanisms of motility and regulation.

PubMed

Maday, Sandra; Twelvetrees, Alison E; Moughamian, Armen J; Holzbaur, Erika L F

2014-10-22

Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of axonal transport pathways and discusses their role in neuronal function.

Axon diameter and intra-axonal volume fraction of the corticospinal tract in idiopathic normal pressure hydrocephalus measured by q-space imaging.

PubMed

Kamiya, Kouhei; Hori, Masaaki; Miyajima, Masakazu; Nakajima, Madoka; Suzuki, Yuriko; Kamagata, Koji; Suzuki, Michimasa; Arai, Hajime; Ohtomo, Kuni; Aoki, Shigeki

2014-01-01

Previous studies suggest that compression and stretching of the corticospinal tract (CST) potentially cause treatable gait disturbance in patients with idiopathic normal pressure hydrocephalus (iNPH). Measurement of axon diameter with diffusion MRI has recently been used to investigate microstructural alterations in neurological diseases. In this study, we investigated alterations in the axon diameter and intra-axonal fraction of the CST in iNPH by q-space imaging (QSI) analysis. Nineteen patients with iNPH and 10 age-matched controls were recruited. QSI data were obtained with a 3-T system by using a single-shot echo planar imaging sequence with the diffusion gradient applied parallel to the antero-posterior axis. By using a two-component low-q fit model, the root mean square displacements of intra-axonal space ( =  axon diameter) and intra-axonal volume fraction of the CST were calculated at the levels of the internal capsule and body of the lateral ventricle, respectively. Wilcoxon's rank-sum test revealed a significant increase in CST intra-axonal volume fraction at the paraventricular level in patients (p<0.001), whereas no significant difference was observed in the axon diameter. At the level of the internal capsule, neither axon diameter nor intra-axonal volume fraction differed significantly between the two groups. Our results suggest that in patients with iNPH, the CST does not undergo irreversible axonal damage but is rather compressed and/or stretched owing to pressure from the enlarged ventricle. These analyses of axon diameter and intra-axonal fraction yield insights into microstructural alterations of the CST in iNPH.

ARF6 directs axon transport and traffic of integrins and regulates axon growth in adult DRG neurons.

PubMed

Eva, Richard; Crisp, Sarah; Marland, Jamie R K; Norman, Jim C; Kanamarlapudi, Venkateswarlu; ffrench-Constant, Charles; Fawcett, James W

2012-07-25

Integrins are involved in axon growth and regeneration. Manipulation of integrins is a route to promoting axon regeneration and understanding regeneration failure in the CNS. Expression of α9 integrin promotes axon regeneration, so we have investigated α9β1 trafficking and transport in axons and at the growth cone. We have previously found that α9 and β1 integrins traffic via Rab11-positive recycling endosomes in peripheral axons and growth cones. However, transport via Rab11 is slow, while rapid transport occurs in vesicles lacking Rab11. We have further studied α9 and β1 integrin transport and traffic in adult rat dorsal root ganglion axons and PC12 cells. Integrins are in ARF6 vesicles during rapid axonal transport and during trafficking in the growth cone. We report that rapid axonal transport of these integrins and their trafficking at the cell surface is regulated by ARF6. ARF6 inactivation by expression of ACAP1 leads to increased recycling of β1 integrins to the neuronal surface and to increased anterograde axonal transport. ARF6 activation by expression of the neuronal guanine nucleotide exchange factors, ARNO or EFA6, increases retrograde integrin transport in axons and increases integrin internalization. ARF6 inactivation increases integrin-mediated outgrowth, while activation decreases it. The coordinated changes in integrin transport and recycling resulting from ARF6 activation or inactivation are the probable mechanism behind this regulation of axon growth. Our data suggest a novel mechanism of integrin traffic and transport in peripheral axons, regulated by the activation state of ARF6, and suggest that ARF6 might be targeted to enhance integrin-dependent axon regeneration after injury.

Indoor A* Pathfinding Through an Octree Representation of a Point Cloud

NASA Astrophysics Data System (ADS)

Rodenberg, O. B. P. M.; Verbree, E.; Zlatanova, S.

2016-10-01

There is a growing demand of 3D indoor pathfinding applications. Researched in the field of robotics during the last decades of the 20th century, these methods focussed on 2D navigation. Nowadays we would like to have the ability to help people navigate inside buildings or send a drone inside a building when this is too dangerous for people. What these examples have in common is that an object with a certain geometry needs to find an optimal collision free path between a start and goal point. This paper presents a new workflow for pathfinding through an octree representation of a point cloud. We applied the following steps: 1) the point cloud is processed so it fits best in an octree; 2) during the octree generation the interior empty nodes are filtered and further processed; 3) for each interior empty node the distance to the closest occupied node directly under it is computed; 4) a network graph is computed for all empty nodes; 5) the A* pathfinding algorithm is conducted. This workflow takes into account the connectivity for each node to all possible neighbours (face, edge and vertex and all sizes). Besides, a collision avoidance system is pre-processed in two steps: first, the clearance of each empty node is computed, and then the maximal crossing value between two empty neighbouring nodes is computed. The clearance is used to select interior empty nodes of appropriate size and the maximal crossing value is used to filter the network graph. Finally, both these datasets are used in A* pathfinding.

Low Piconewton Towing of CNS Axons against Diffusing and Surface-Bound Repellents Requires the Inhibition of Motor Protein-Associated Pathways

NASA Astrophysics Data System (ADS)

Kilinc, Devrim; Blasiak, Agata; O'Mahony, James J.; Lee, Gil U.

2014-11-01

Growth cones, dynamic structures at axon tips, integrate chemical and physical stimuli and translate them into coordinated axon behaviour, e.g., elongation or turning. External force application to growth cones directs and enhances axon elongation in vitro; however, direct mechanical stimulation is rarely combined with chemotactic stimulation. We describe a microfluidic device that exposes isolated cortical axons to gradients of diffusing and substrate-bound molecules, and permits the simultaneous application of piconewton (pN) forces to multiple individual growth cones via magnetic tweezers. Axons treated with Y-27632, a RhoA kinase inhibitor, were successfully towed against Semaphorin 3A gradients, which repel untreated axons, with less than 12 pN acting on a small number of neural cell adhesion molecules. Treatment with Y-27632 or monastrol, a kinesin-5 inhibitor, promoted axon towing on substrates coated with chondroitin sulfate proteoglycans, potent axon repellents. Thus, modulating key molecular pathways that regulate contractile stress generation in axons counteracts the effects of repellent molecules and promotes tension-induced growth. The demonstration of parallel towing of axons towards inhibitory environments with minute forces suggests that mechanochemical stimulation may be a promising therapeutic approach for the repair of the damaged central nervous system, where regenerating axons face repellent factors over-expressed in the glial scar.

Time course of ongoing activity during neuritis and following axonal transport disruption.

PubMed

Satkeviciute, Ieva; Goodwin, George; Bove, Geoffrey M; Dilley, Andrew

2018-05-01

Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (<10%) A- and C-fiber neurons showed ongoing activity 1-15 days following vinblastine treatment. In contrast, AMS increased transiently at the vinblastine treatment site, peaking on days 4-5 (28% of C/slow Aδ-fiber neurons) and resolved by day 15. Conduction velocities were slowed in all groups. In summary, the disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.

Pathfinder-Plus aircraft in flight

NASA Technical Reports Server (NTRS)

1998-01-01

The Pathfinder-Plus solar-powered aircraft is shown taking off from a runway, then flying at low altitude over the ocean. The vehicle, which looks like a flying ruler, operates at low airspeed. Among the missions proposed for a solar-powered aircraft are communications relay, atmospheric studies, pipeline monitoring and gas leak detection, environmental monitoring using thermal and radar images, and disaster relief and monitoring.

Predictive Validity of Measures of the Pathfinder Scaling Algorithm on Programming Performance: Alternative Assessment Strategy for Programming Education

ERIC Educational Resources Information Center

Lau, Wilfred W. F.; Yuen, Allan H. K.

2009-01-01

Recent years have seen a shift in focus from assessment of learning to assessment for learning and the emergence of alternative assessment methods. However, the reliability and validity of these methods as assessment tools are still questionable. In this article, we investigated the predictive validity of measures of the Pathfinder Scaling…

Pathfinders and Problem Solving: Comparative Effects of Two Cognitive-Behavioral Programs among Men and Women Offenders in Community and Prison

ERIC Educational Resources Information Center

Spiropoulos, Georgia V.; Spruance, Lisa; Van Voorhis, Patricia; Schmitt, Michelle M.

2005-01-01

The effects of "Problem Solving" (Taymans & Parese, 1998) are compared across small diversion and prison samples for men and women. A second program, "Pathfinders" (Hansen, 1993), was compared to the Problem Solving program among incarcerated women offenders to determine whether its focus upon empowerment and relationships enhanced the effects of…

Sojourner Rover View of Pathfinder Lander

NASA Technical Reports Server (NTRS)

1997-01-01

Image of Pathfinder Lander on Mars taken from Sojourner Rover left front camera on sol 33. The IMP (on the lattice mast) is looking at the rover. Airbags are prominent, and the meteorology mast is shown to the right. Lowermost rock is Ender, with Hassock behind it and Yogi on the other side of the lander.

NOTE: original caption as published in Science Magazine

A Review of Solar-Powered Aircraft Flight Activity at the Pacific Missile Range Test Facility, Kauai, Hawaii

NASA Technical Reports Server (NTRS)

Ehernberger, L. J.; Donohue, Casey; Teets, Edward H., Jr.

2004-01-01

A series of solar-powered aircraft have been designed and operated by AeroVironment, Inc. (Monrovia, CA) as a part of National Aeronautics and Space Administration (NASA) objectives to develop energy-efficient high-altitude long-endurance platforms for earth observations and communications applications. Flight operations have been conducted at NASA's Dryden Flight Research Center, Edwards CA and at the U.S. Navy Pacific Missile Range Facility (PMRF) at Barking Sands, Kauai, HI. These aircraft flown at PMRF are named Pathfinder , Pathfinder Plus and Helios . Sizes of these three aircraft range from 560 lb with a 99-ft wingspan to 2300 lb with a 247-ft wingspan. Available payload capacity reaches approximately 200 lb. Pathfinder uses six engines and propellers: Pathfinder Plus 8; and Helios 14. The 2003 Helios fuel cell configurations used 10 engines and propellers. The PMRF was selected as a base of operations because if offers optimal summertime solar exposure, low prevailing wind-speeds on the runway, modest upper-air wind-speeds and the availability of suitable airspace. Between 1997 and 2001, successive altitude records of 71,530 ft, 80,200 ft, and 96,863 ft were established. Flight durations extended to 18 hours.

A Study to Compare the Failure Rates of Current Space Shuttle Ground Support Equipment with the New Pathfinder Equipment and Investigate the Effect that the Proposed GSE Infrastructure Upgrade Might Have to Reduce GSE Infrastructure Failures

NASA Technical Reports Server (NTRS)

Kennedy, Barbara J.

2004-01-01

The purposes of this study are to compare the current Space Shuttle Ground Support Equipment (GSE) infrastructure with the proposed GSE infrastructure upgrade modification. The methodology will include analyzing the first prototype installation equipment at Launch PAD B called the "Pathfinder". This study will begin by comparing the failure rate of the current components associated with the "Hardware interface module (HIM)" at the Kennedy Space Center to the failure rate of the neW Pathfinder components. Quantitative data will be gathered specifically on HIM components and the PAD B Hypergolic Fuel facility and Hypergolic Oxidizer facility areas which has the upgraded pathfinder equipment installed. The proposed upgrades include utilizing industrial controlled modules, software, and a fiber optic network. The results of this study provide evidence that there is a significant difference in the failure rates of the two studied infrastructure equipment components. There is also evidence that the support staff for each infrastructure system is not equal. A recommendation to continue with future upgrades is based on a significant reduction of failures in the new' installed ground system components.

Localization of mRNA in vertebrate axonal compartments by in situ hybridization.

PubMed

Sotelo-Silveira, José Roberto; Calliari, Aldo; Kun, Alejandra; Elizondo, Victoria; Canclini, Lucía; Sotelo, José Roberto

2011-01-01

The conclusive demonstration of RNA in vertebrate axons by in situ hybridization (ISH) has been elusive. We review the most important reasons for difficulties, including low concentration of axonal RNAs, localization in specific cortical domains, and the need to isolate axons. We demonstrate the importance of axon micro-dissection to obtain a whole mount perspective of mRNA distribution in the axonal territory. We describe a protocol to perform fluorescent ISH in isolated axons and guidelines for the preservation of structural and molecular integrity of cortical RNA-containing domains (e.g., Periaxoplasmic Ribosomal Plaques, or PARPs) in isolated axoplasm.

Selective rab11 transport and the intrinsic regenerative ability of CNS axons

PubMed Central

Koseki, Hiroaki; Donegá, Matteo; Lam, Brian YH; Petrova, Veselina; van Erp, Susan; Yeo, Giles SH; Kwok, Jessica CF; ffrench-Constant, Charles

2017-01-01

Neurons lose intrinsic axon regenerative ability with maturation, but the mechanism remains unclear. Using an in-vitro laser axotomy model, we show a progressive decline in the ability of cut CNS axons to form a new growth cone and then elongate. Failure of regeneration was associated with increased retraction after axotomy. Transportation into axons becomes selective with maturation; we hypothesized that selective exclusion of molecules needed for growth may contribute to regeneration decline. With neuronal maturity rab11 vesicles (which carry many molecules involved in axon growth) became selectively targeted to the somatodendritic compartment and excluded from axons by predominant retrograde transport However, on overexpression rab11 was mistrafficked into proximal axons, and these axons showed less retraction and enhanced regeneration after axotomy. These results suggest that the decline of intrinsic axon regenerative ability is associated with selective exclusion of key molecules, and that manipulation of transport can enhance regeneration. PMID:28829741

Inhibiting poly(ADP-ribosylation) improves axon regeneration.

PubMed

Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi; Strittmatter, Stephen M; Miller, David M; Hammarlund, Marc

2016-10-04

The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration.

Inhibiting poly(ADP-ribosylation) improves axon regeneration

PubMed Central

Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi; Strittmatter, Stephen M; Miller, David M; Hammarlund, Marc

2016-01-01

The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration. DOI: http://dx.doi.org/10.7554/eLife.12734.001 PMID:27697151

In Vitro Analysis of the Role of Schwann Cells on Axonal Degeneration and Regeneration Using Sensory Neurons from Dorsal Root Ganglia.

PubMed

López-Leal, Rodrigo; Diaz, Paula; Court, Felipe A

2018-01-01

Sensory neurons from dorsal root ganglion efficiently regenerate after peripheral nerve injuries. These neurons are widely used as a model system to study degenerative mechanisms of the soma and axons, as well as regenerative axonal growth in the peripheral nervous system. This chapter describes techniques associated to the study of axonal degeneration and regeneration using explant cultures of dorsal root ganglion sensory neurons in vitro in the presence or absence of Schwann cells. Schwann cells are extremely important due to their involvement in tissue clearance during axonal degeneration as well as their known pro-regenerative effect during regeneration in the peripheral nervous system. We describe methods to induce and study axonal degeneration triggered by axotomy (mechanical separation of the axon from its soma) and treatment with vinblastine (which blocks axonal transport), which constitute clinically relevant mechanical and toxic models of axonal degeneration. In addition, we describe three different methods to evaluate axonal regeneration using quantitative methods. These protocols constitute a valuable tool to analyze in vitro mechanisms associated to axonal degeneration and regeneration of sensory neurons and the role of Schwann cells in these processes.

Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collin, Ludovic; Doretto, Sandrine; Department of Psychiatry and Human Behavior, University of California Irvine, 3226 Gillespie Neuroscience Research Facility, Irvine CA 92697

2007-08-01

Oligodendrocytes (OLs) are the glial cells of the central nervous system (CNS) classically known to be devoted to the formation of myelin sheaths around most axons of the vertebrate brain. We have addressed the role of these cells during cerebellar development, by ablating OLs in vivo. Previous analyses had indicated that OL ablation during the first six postnatal days results into a striking cerebellar phenotype, whose major features are a strong reduction of granule neurons and aberrant Purkinje cells development. These two cell types are highly interconnected during cerebellar development through the production of molecules that help their proliferation, differentiationmore » and maintenance. In this article, we present data showing that OL ablation has major effects on the physiology of Purkinje (PC) and granule cells (GC). In particular, OL ablation results into a reduction of sonic hedgehog (Shh), Brain Derived Neurotrophic Factor (BDNF), and Reelin (Rln) expression. These results indicate that absence of OLs profoundly alters the normal cerebellar developmental program.« less

Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism.

PubMed

Davis, Peter E; Peters, Jurriaan M; Krueger, Darcy A; Sahin, Mustafa

2015-07-01

Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.

Peroxisomes in brain development and function☆

PubMed Central

Berger, Johannes; Dorninger, Fabian; Forss-Petter, Sonja; Kunze, Markus

2016-01-01

Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer’s disease, autism and amyotrophic lateral sclerosis. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann. PMID:26686055

Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes.

PubMed

Katyal, Sachin; Lee, Youngsoo; Nitiss, Karin C; Downing, Susanna M; Li, Yang; Shimada, Mikio; Zhao, Jingfeng; Russell, Helen R; Petrini, John H J; Nitiss, John L; McKinnon, Peter J

2014-06-01

DNA damage is considered to be a prime factor in several spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. We observed the endogenous accumulation of pathogenic topoisomerase-1 (Top1)-DNA cleavage complexes (Top1ccs) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We found that the defective DNA damage response factors in these two diseases cooperatively modulated Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single-strand break repair factors, including tyrosyl-DNA phosphodiesterase-1 or XRCC1, resulted in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Notably, direct Top1 poisoning to elevate Top1cc levels phenocopied the neuropathology of the mouse models described above. Our results identify a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating that genome integrity is important for preventing disease in the nervous system.

Hypoglossal-facial nerve reconstruction using a Y-tube-conduit reduces aberrant synkinetic movements of the orbicularis oculi and vibrissal muscles in rats.

PubMed

Kaya, Yasemin; Ozsoy, Umut; Turhan, Murat; Angelov, Doychin N; Sarikcioglu, Levent

2014-01-01

The facial nerve is the most frequently damaged nerve in head and neck trauma. Patients undergoing facial nerve reconstruction often complain about disturbing abnormal synkinetic movements of the facial muscles (mass movements, synkinesis) which are thought to result from misguided collateral branching of regenerating motor axons and reinnervation of inappropriate muscles. Here, we examined whether use of an aorta Y-tube conduit during reconstructive surgery after facial nerve injury reduces synkinesis of orbicularis oris (blink reflex) and vibrissal (whisking) musculature. The abdominal aorta plus its bifurcation was harvested (N = 12) for Y-tube conduits. Animal groups comprised intact animals (Group 1), those receiving hypoglossal-facial nerve end-to-end coaptation alone (HFA; Group 2), and those receiving hypoglossal-facial nerve reconstruction using a Y-tube (HFA-Y-tube, Group 3). Videotape motion analysis at 4 months showed that HFA-Y-tube group showed a reduced synkinesis of eyelid and whisker movements compared to HFA alone.

Hypoglossal-Facial Nerve Reconstruction Using a Y-Tube-Conduit Reduces Aberrant Synkinetic Movements of the Orbicularis Oculi and Vibrissal Muscles in Rats

PubMed Central

Kaya, Yasemin; Ozsoy, Umut; Turhan, Murat; Angelov, Doychin N.; Sarikcioglu, Levent

2014-01-01

The facial nerve is the most frequently damaged nerve in head and neck trauma. Patients undergoing facial nerve reconstruction often complain about disturbing abnormal synkinetic movements of the facial muscles (mass movements, synkinesis) which are thought to result from misguided collateral branching of regenerating motor axons and reinnervation of inappropriate muscles. Here, we examined whether use of an aorta Y-tube conduit during reconstructive surgery after facial nerve injury reduces synkinesis of orbicularis oris (blink reflex) and vibrissal (whisking) musculature. The abdominal aorta plus its bifurcation was harvested (N = 12) for Y-tube conduits. Animal groups comprised intact animals (Group 1), those receiving hypoglossal-facial nerve end-to-end coaptation alone (HFA; Group 2), and those receiving hypoglossal-facial nerve reconstruction using a Y-tube (HFA-Y-tube, Group 3). Videotape motion analysis at 4 months showed that HFA-Y-tube group showed a reduced synkinesis of eyelid and whisker movements compared to HFA alone. PMID:25574468

Extreme Rock Distributions on Mars and Implications for Landing Safety

NASA Technical Reports Server (NTRS)

Golombek, M. P.

2001-01-01

Prior to the landing of Mars Pathfinder, the size-frequency distribution of rocks from the two Viking landing sites and Earth analog surfaces was used to derive a size-frequency model, for nomimal rock distributions on Mars. This work, coupled with extensive testing of the Pathfinder airbag landing system, allowed an estimate of what total rock abundances derived from thermal differencing techniques could be considered safe for landing. Predictions based on this model proved largely correct at predicting the size-frequency distribution of rocks at the Mars Pathfinder site and the fraction of potentially hazardous rocks. In this abstract, extreme rock distributions observed in Mars Orbiter Camera (MOC) images are compared with those observed at the three landing sites and model distributions as an additional constraint on potentially hazardous surfaces on Mars.

Rock Garden

NASA Technical Reports Server (NTRS)

1997-01-01

This false color composite image of the Rock Garden shows the rocks 'Shark' and 'Half Dome' at upper left and middle, respectively. Between these two large rocks is a smaller rock (about 0.20 m wide, 0.10 m high, and 6.33 m from the Lander) that was observed close-up with the Sojourner rover (see PIA00989).

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Diversity of soils near rover deploy region

NASA Technical Reports Server (NTRS)

1997-01-01

The surface near the rover's egress from the lander contains mainly bright red drift (#1), dark gray rocks such as Cradle (# 3), soil intermediate in color to the rocks and drift (#2), and dark red soil on and around the rock Lamb (#4). Globally, Mars is characterized by similar color variations. The spectra, measured using the full 13-color capability of the Imager for Mars Pathfinder (IMP), provide evidence for the mineralogy of the unweathered rocks and highly weathered red soils.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech).

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, contracted by Goodloe Transportation of Chicago, travels along the NASA railroad bridge over the Indian River north of Kennedy Space Center, carrying one of two containers on a railcar for transport to the NASA Jay Jay railroad yard. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the Rotation, Processing and Surge Facility (RPSF). Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, conracted by Goodloe Transportation of Chicago, travels along the NASA railroad bridge over the Indian River north of Kennedy Space Center, with two containers on railcars for transport to the NASA Jay Jay railroad yard. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the Rotation, Processing and Surge Facility (RPSF). Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, contracted by Goodloe Transportation of Chicago, approaches the raised span of the NASA railroad bridge to continue over the Indian River north of Kennedy Space Center with two containers on railcars for storage at the NASA Jay Jay railroad yard. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the Rotation, Processing and Surge Facility (RPSF). Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, contracted by Goodloe Transportation of Chicago, travels along the NASA railroad bridge over the Indian River north of Kennedy Space Center, carrying one of two containers on a railcar for transport to the NASA Jay Jay railroad yard near the center. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the Rotation, Processing and Surge Facility (RPSF). Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

SLS Pathfinder Segments Car Train Departure

NASA Image and Video Library

2016-03-02

An Iowa Northern locomotive, contracted by Goodloe Transportation of Chicago, continues along the NASA railroad bridge over the Indian River north of Kennedy Space Center, carrying one of two containers on a railcar for transport to the NASA Jay Jay railroad yard. The containers held two pathfinders, or test versions, of solid rocket booster segments for NASA’s Space Launch System rocket that were delivered to the Rotation, Processing and Surge Facility (RPSF). Inside the RPSF, the Ground Systems Development and Operations Program and Jacobs Engineering, on the Test and Operations Support Contract, will conduct a series of lifts, moves and stacking operations using the booster segments, which are inert, to prepare for Exploration Mission-1, deep-space missions and the journey to Mars. The pathfinder booster segments are from Orbital ATK in Utah.

Marie Curie during ORT4

NASA Technical Reports Server (NTRS)

2003-01-01

Marie Curie rover drives down the rear ramp during Operational Readiness Test (ORT) 4.

Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars over thenext ten years. Mars Global Surveyor, already en route, arrives at Mars on September 11 to begin a two year orbital reconnaissance of the planet's composition, topography, and climate. Additional orbiters and landers will follow every 26 months.

The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Axonal abnormalities in vanishing white matter.

PubMed

Klok, Melanie D; Bugiani, Marianna; de Vries, Sharon I; Gerritsen, Wouter; Breur, Marjolein; van der Sluis, Sophie; Heine, Vivi M; Kole, Maarten H P; Baron, Wia; van der Knaap, Marjo S

2018-04-01

We aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. Axons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. In the corpus callosum of Eif2b5- mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5- mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5 -mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. In vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

In vivo imaging reveals mitophagy independence in the maintenance of axonal mitochondria during normal aging.

PubMed

Cao, Xu; Wang, Haiqiong; Wang, Zhao; Wang, Qingyao; Zhang, Shuang; Deng, Yuanping; Fang, Yanshan

2017-10-01

Mitophagy is thought to be a critical mitochondrial quality control mechanism in neurons and has been extensively studied in neurological disorders such as Parkinson's disease. However, little is known about how mitochondria are maintained in the lengthy neuronal axons in the context of physiological aging. Here, we utilized the unique Drosophila wing nerve model and in vivo imaging to rigorously profile changes in axonal mitochondria during aging. We revealed that mitochondria became fragmented and accumulated in aged axons. However, lack of Pink1 or Parkin did not lead to the accumulation of axonal mitochondria or axonal degeneration. Further, unlike in in vitro cultured neurons, we found that mitophagy rarely occurred in intact axons in vivo, even in aged animals. Furthermore, blocking overall mitophagy by knockdown of the core autophagy genes Atg12 or Atg17 had little effect on the turnover of axonal mitochondria or axonal integrity, suggesting that mitophagy is not required for axonal maintenance; this is regardless of whether the mitophagy is PINK1-Parkin dependent or independent. In contrast, downregulation of mitochondrial fission-fusion genes caused age-dependent axonal degeneration. Moreover, Opa1 expression in the fly head was significantly decreased with age, which may underlie the accumulation of fragmented mitochondria in aged axons. Finally, we showed that adult-onset, neuronal downregulation of the fission-fusion, but not mitophagy genes, dramatically accelerated features of aging. We propose that axonal mitochondria are maintained independently of mitophagy and that mitophagy-independent mechanisms such as fission-fusion may be central to the maintenance of axonal mitochondria and neural integrity during normal aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Dependence of regenerated sensory axons on continuous neurotrophin-3 delivery.

PubMed

Hou, Shaoping; Nicholson, LaShae; van Niekerk, Erna; Motsch, Melanie; Blesch, Armin

2012-09-19

Previous studies have shown that injured dorsal column sensory axons extend across a spinal cord lesion site if axons are guided by a gradient of neurotrophin-3 (NT-3) rostral to the lesion. Here we examined whether continuous NT-3 delivery is necessary to sustain regenerated axons in the injured spinal cord. Using tetracycline-regulated (tet-off) lentiviral gene delivery, NT-3 expression was tightly controlled by doxycycline administration. To examine axon growth responses to regulated NT-3 expression, adult rats underwent a C3 dorsal funiculus lesion. The lesion site was filled with bone marrow stromal cells, tet-off-NT-3 virus was injected rostral to the lesion site, and the intrinsic growth capacity of sensory neurons was activated by a conditioning lesion. When NT-3 gene expression was turned on, cholera toxin β-subunit-labeled sensory axons regenerated into and beyond the lesion/graft site. Surprisingly, the number of regenerated axons significantly declined when NT-3 expression was turned off, whereas continued NT-3 expression sustained regenerated axons. Quantification of axon numbers beyond the lesion demonstrated a significant decline of axon growth in animals with transient NT-3 expression, only some axons that had regenerated over longer distance were sustained. Regenerated axons were located in white matter and did not form axodendritic synapses but expressed presynaptic markers when closely associated with NG2-labeled cells. A decline in axon density was also observed within cellular grafts after NT-3 expression was turned off possibly via reduction in L1 and laminin expression in Schwann cells. Thus, multiple mechanisms underlie the inability of transient NT-3 expression to fully sustain regenerated sensory axons.

Piezoelectric ceramic (PZT) modulates axonal guidance growth of rat cortical neurons via RhoA, Rac1, and Cdc42 pathways.

PubMed

Wen, Jianqiang; Liu, Meili

2014-03-01

Electrical stimulation is critical for axonal connection, which can stimulate axonal migration and deformation to promote axonal growth in the nervous system. Netrin-1, an axonal guidance cue, can also promote axonal guidance growth, but the molecular mechanism of axonal guidance growth under indirect electric stimulation is still unknown. We investigated the molecular mechanism of axonal guidance growth under piezoelectric ceramic lead zirconate titanate (PZT) stimulation in the primary cultured cortical neurons. PZT induced marked axonal elongation. Moreover, PZT activated the excitatory postsynaptic currents (EPSCs) by increasing the frequency and amplitude of EPSCs of the cortical neurons in patch clamp assay. PZT downregulated the expression of Netrin-1 and its receptor Deleted in Colorectal Cancer (DCC). Rho GTPase signaling is involved in interactions of Netrin-1 and DCC. PZT activated RhoA. Dramatic decrease of Cdc42 and Rac1 was also observed after PZT treatment. RhoA inhibitor Clostridium botulinum C3 exoenzyme (C3-Exo) prevented the PZT-induced downregulation of Netrin-1 and DCC. We suggest that PZT can promote axonal guidance growth by downregulation of Netrin-1 and DCC to mediate axonal repulsive responses via the Rho GTPase signaling pathway. Obviously, piezoelectric materials may provide a new approach for axonal recovery and be beneficial for clinical therapy in the future.

Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons

NASA Technical Reports Server (NTRS)

Kirkpatrick, L. L.; Witt, A. S.; Payne, H. R.; Shine, H. D.; Brady, S. T.

2001-01-01

Altered axon-Schwann cell interactions in PNS myelin-deficient Trembler mice result in changed axonal transport rates, neurofilament and microtubule-associated protein phosphorylation, neurofilament density, and microtubule stability. To determine whether PNS and CNS myelination have equivalent effects on axons, neurofilaments, and microtubules in CNS, myelin-deficient shiverer axons were examined. The genetic defect in shiverer is a deletion in the myelin basic protein (MBP) gene, an essential component of CNS myelin. As a result, shiverer mice have little or no compact CNS myelin. Slow axonal transport rates in shiverer CNS axons were significantly increased, in contrast to the slowing in demyelinated PNS nerves. Even more striking were substantial changes in the composition and properties of microtubules in shiverer CNS axons. The density of axonal microtubules is increased, reflecting increased expression of tubulin in shiverer, and the stability of microtubules is drastically reduced in shiverer axons. Shiverer transgenic mice with two copies of a wild-type myelin basic protein transgene have an intermediate level of compact myelin, making it possible to determine whether the actual level of compact myelin is an important regulator of axonal microtubules. Both increased microtubule density and reduced microtubule stability were still observed in transgenic mouse nerves, indicating that signals beyond synaptogenesis and the mere presence of compact myelin are required for normal regulation of the axonal microtubule cytoskeleton.

A morphological study of diffuse axonal injury in a rat model by lateral head rotation trauma.

PubMed

Xiaoshengi, He; Guitao, Yang; Xiang, Zhang; Zhou, Fei

2010-03-01

Morphology in diffuse axonal injury (DAI) by lateral head rotation was investigated. SD rats were divided into injury (n=9) and sham (n=3) groups. A device was used to produce lateral rotational acceleration of the rats' heads. At different survival times three rats were killed for light and electron microscopic examination of the brain tissue. Sagittal sections were made from medulla oblongata and immunolabelled for NF68. At post-traumatic 30 min, NF68 immunolabelling showed a small number ofswollen and irregular axons. Ultrastructurally slightly-separated myelin lamellae and disorderly arranged neurofilaments occurred. At 2 and 24 h axonal damage became more severe. Increases in immunolabelled axonal swellings, disconnected axons and axonal retraction bulbs appeared. EM provided evidence of myelin separation, peri-axonal spaces, blank areas in axoplasm, loss of microtubules, peripheral accumulation of mitochondria and clumped neurofilaments for DAI. A tendency was noted for greater labelling with NF68 as axonal damage increased. The disorderly arrangement of NFs occurred at early stage of post-traumatic axonal changes.

S6 Kinase Inhibits Intrinsic Axon Regeneration Capacity via AMP Kinase in Caenorhabditis elegans

PubMed Central

Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D.

2014-01-01

The ability of axons to regrow after injury is determined by the complex interplay of intrinsic growth programs and external cues. In Caenorhabditis elegans mechanosensory neuron, axons exhibit robust regenerative regrowth following laser axotomy. By surveying conserved metabolic signaling pathways, we have identified the ribosomal S6 kinase RSKS-1 as a new cell-autonomous inhibitor of axon regeneration. RSKS-1 is not required for axonal development but inhibits axon regrowth after injury in multiple neuron types. Loss of function in rsks-1 results in more rapid growth cone formation after injury and accelerates subsequent axon extension. The enhanced regrowth of rsks-1 mutants is partly dependent on the DLK-1 MAPK cascade. An essential output of RSKS-1 in axon regrowth is the metabolic sensor AMP kinase, AAK-2. We further show that the antidiabetic drug phenformin, which activates AMP kinase, can promote axon regrowth. Our data reveal a new function for an S6 kinase acting through an AMP kinase in regenerative growth of injured axons. PMID:24431434

GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules

PubMed Central

Hur, Eun-Mi; Saijilafu; Lee, Byoung Dae; Kim, Seong-Jin; Xu, Wen-Lin; Zhou, Feng-Quan

2011-01-01

Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs. PMID:21937714

LISA Pathfinder

NASA Technical Reports Server (NTRS)

Stebbins, Robin

2008-01-01

USA Pathfinder is a space mission dedicated to demonstrating technology for the Laser Interferometer Space Antenna (LISA). LISA is a joint ESA/NASA mission to detect low-frequency gravitational waves on the 0.0001 to 0.1 Hz frequency band. LISA is expected to observe 100's of merging massive black hole binaries out z-15, tens of thousands of close compact binary systems in the Milky Way, merging intermediate-mass black hole binaries, tens of stellar-mass black holes falling into supermassive black holes in galactic centers, and possibly other exotic sources. Several critical LISA technologies have not been demonstrated at the requisite level of performance. In spaceflight, and some fight hardware cannot be tested in a 1-g environment. Hence, the LISA Pathfinder mission is being implemented to demonstrate these critical LISA technologies in a relevant flight environment. LISA Pathfinder mimics one arm of the LISA constellation by shrinking the 5-million-kilometer armlength down to a few tens of centimeters. The experimental concept is to measure the relative separation between two test masses nominally following their own geodesics, and thereby determine the relative residual acceleration between them near 1 mHz, about a decade above the lowest frequency required by LISA. To implement such a concept, disturbances on the test masses must be kept very small by many design features, but chiefly by "drag-free" flight. A drag-free spacecraft follows a free-falling test mass which it encloses, but has no mechanical connection to. The spacecraft senses it's orientation and separation with respect to the proof mass, and its propulsion system is commanded to keep the spacecraft centered about the test mass. Thus, the spacecraft shields the test mass from most external influences, and minimizes the effect of force gradients arising from the spacecraft, and acting on the test mass. LISA Pathfinder will compare the geodesic of one test mass against that of the other. Only a metrology system based on interferometry can achieve the displacement sensitivity. Interferometers monitor the separation of both test masses with a sensitivity comparable to that required by LISA, and using the same technologies. LISA Pathfinder is scheduled to be launched in the first half of 1020 to a Lissajous orbit around the first Sun-Earth Lagrange point, L1. In addition to a complete European technology package (the LISA Technology Package, or LTP), LISA Pathfinder will also carry thrusters and software, known as ST-7, a part of NASA's New Millennium Program.

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination.

PubMed

Schultz, Verena; van der Meer, Franziska; Wrzos, Claudia; Scheidt, Uta; Bahn, Erik; Stadelmann, Christine; Brück, Wolfgang; Junker, Andreas

2017-08-01

Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin-induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

Cerebellar afferents originating from the medullary reticular formation that are different from mossy, climbing or monoaminergic fibers in the rat.

PubMed

Luo, Yuanjun; Sugihara, Izumi

2014-05-30

Integration of cortical Purkinje cell inputs and brain stem inputs is essential in generating cerebellar outputs to the cerebellar nuclei (CN). Currently, collaterals of climbing and mossy fiber axons, noradrenergic, serotoninergic and cholinergic axons, and collaterals of rubrospinal axons are known to innervate the CN from the brain stem. We investigated whether other afferents to the CN from the medulla exist in the rat. Retrograde labeling revealed the presence of neurons that project to the CN but not to the cerebellar cortex in the median reticular formation in the rostrodorsal medulla (tentatively named 'caudal raphe interpositus area', CRI). Anterograde tracer injection into the CRI labeled abundant axonal terminals in the CN, mainly in the ventral parvocellular part of the posterior interposed and lateral nucleus. Axonal reconstruction showed that a single CRI axon projected to the CN with 170-1086 varicosities, more broadly and densely than collaterals of a mossy or climbing fiber axon. CRI axons had no or a few collaterals that projected to the granular and Purkinje cell layers of the cerebellar cortex with some small terminals, indicating that these axons are different from mossy fiber axons. CRI axons also had collaterals that projected to the medial vestibular nucleus and an ascending branch that was not reconstructed. The location of the CRI, electron microscopic observations, and immunostaining results all indicated that CRI axons are not monoaminergic. We conclude that CRI axons form a type of afferent projection to the CN that is different from mossy, climbing or monoaminergic fibers. Copyright © 2014 Elsevier B.V. All rights reserved.

Cryogenic Test Technology 1984.

DTIC Science & Technology

1985-04-01

requirements. The material selection for the Pathfinder I was further restricted by long delivery times before Nitronic 40 was chosen. The alloys under...severe requirements of cryogenic model building. A detailed study of the characteristics of Nitronic 40 is reported in reference 36. This paper, and...remarks elsewhere about experience with Pathfinder I (made from Nitronic 40 ), suggest that quality control problems were encountered with at least one batch

JPL Experience with the Mars Pathfinder, Mission Simulation Battery

NASA Technical Reports Server (NTRS)

Perrone, Dave; Ewell, Richard

1997-01-01

A summary of the Mars Pathfinder Battery is given. The battery survived 47 days at 25 deg. C; it survived a 7 month stand at 10 to -5 deg. C; it met and exceeded 40 ampere-hour capacity for EDL; it met the 30 cycle minimum for Mars surface operation; and the project power profile for MArs surface operation does not yield energy balance.

Mars Pathfinder Landing Site Workshop 2: Characteristics of the Ares Vallis Region and Field Trips in the Channeled Scabland, Washington

NASA Technical Reports Server (NTRS)

Golombek, M. P. (Editor); Edgett, K. S. (Editor); Rice, J. W. , Jr. (Editor)

1995-01-01

Mars Pathfinder will place a single lander on the surface of Mars on July 4, 1997, following a December 1996 launch. As a result of the very successful first Mars Pathfinder Landing Site Workshop, the project has selected the Ares Vallis outflow channel in Chryse Planitia as the landing site. This location is where a large catastrophic outflow channel debouches into the northern lowlands. A second workshop and series of field trips, entitled Mars Pathfinder Landing Site Workshop 2: Characteristics of the Ares Vallis Region and Field Trips in the Channeled Scabland, Washington, were held in Spokane and Moses Lake, Washington. The purpose of the workshop was to provide a focus for learning as much as possible about the Ares Vallis region on Mars before landing there. The rationale is that the more that can be learned about the general area prior to landing, the better scientists will be able interpret the observations made by the lander and rover and place them in the proper geologic context. The field trip included overflights and surface investigations of the Channeled Scabland (an Earth analog for the martian catastrophic outflow channels), focusing on areas particularly analogous to Ares Vallis and the landing site. The overflights were essential for placing the enormous erosional and depositional features of the Channeled Scabland into proper three-dimensional context. The field trips were a joint educational outreach activity involving K-12 science educators, Mars Pathfinder scientists and engineers, and interested scientists from the Mars scientific community. Part 1 of the technical report on this workshop includes a description of the Mars Pathfinder mission, abstracts accepted for presentation at the workshop, an introduction to the Channeled Scabland, and field trip guides for the overflight and two field trips. This part, Part 2, includes the program for the workshop, summaries of the workshop technical sessions, a summary of the field trips and ensuing discussions, late abstracts of workshop presentations, reports on the education and public outreach activities carried out by the educators, and a list of the workshop and field trip participants.

Future X Pathfinder: Quick, Low Cost Flight Testing for Tomorrow's Launch Vehicles

NASA Technical Reports Server (NTRS)

London, John, III; Sumrall, Phil

1999-01-01

The DC-X and DC-XA Single Stage Technology flight program demonstrated the value of low cost rapid prototyping and flight testing of launch vehicle technology testbeds. NASA is continuing this important legacy through a program referred to as Future-X Pathfinder. This program is designed to field flight vehicle projects that cost around $100M each, with a new vehicle flying about every two years. Each vehicle project will develop and extensively flight test a launch vehicle technology testbed that will advance the state of the art in technologies directly relevant to future space transportation systems. There are currently two experimental, or "X" vehicle projects in the Pathfinder program, with additional projects expected to follow in the near future. The first Pathfinder project is X-34. X-34 is a suborbital rocket plane capable of flights to Mach 8 and 75 kilometers altitude. There are a number of reusable launch vehicle technologies embedded in the X-34 vehicle design, such as composite structures and propellant tanks, and advanced reusable thermal protection systems. In addition, X-34 is designed to carry experiments applicable to both the launch vehicle and hypersonic aeronautics community. X-34 is scheduled to fly later this year. The second Pathfinder project is the X-37. X-37 is an orbital space plane that is carried into orbit either by the Space Shuttle or by an expendable launch vehicle. X-37 provides NASA access to the orbital and orbital reentry flight regimes with an experimental testbed vehicle. The vehicle will expose embedded and carry-on advanced space transportation technologies to the extreme environments of orbit and reentry. Early atmospheric approach and landing tests of an unpowered version of the X-37 will begin next year, with orbital flights beginning in late 2001. Future-X Pathfinder is charting a course for the future with its growing fleet of low-cost X- vehicles. X-34 and X-37 are leading the assault on high launch costs and enabling the flight testing of technologies that will lead to affordable access to space.

Premyelinated central axons express neurotoxic NMDA receptors: relevance to early developing white-matter injury

PubMed Central

Huria, Tahani; Beeraka, Narasimha Murthy; Al-Ghamdi, Badrah; Fern, Robert

2015-01-01

Ischemic-type injury to developing white matter is associated with the significant clinical condition cerebral palsy and with the cognitive deficits associated with premature birth. Premyelinated axons are the major cellular component of fetal white matter and loss of axon function underlies the disability, but the cellular mechanisms producing ischemic injury to premyelinated axons have not previously been described. Injury was found to require longer periods of modelled ischemia than at latter developmental points. Ischemia produced initial hyperexcitability in axons followed by loss of function after Na+ and Ca2+ influx. N-methyl-D-aspartate- (NMDA) type glutamate receptor (GluR) agonists potentiated axon injury while antagonists were protective. The NMDA GluR obligatory Nr1 subunit colocalized with markers of small premyelinated axons and expression was found at focal regions of axon injury. Ischemic injury of glial cells present in early developing white matter was NMDA GluR independent. Axons in human postconception week 18 to 23 white matter had a uniform prediameter expansion phenotype and postembedded immuno-gold labelling showed Nr1 subunit expression on the membrane of these axons, demonstrating a shared key neuropathologic feature with the rodent model. Premyelinated central axons therefore express high levels of functional NMDA GluRs that confer sensitivity to ischemic injury. PMID:25515212

Demonstration of ion channel synthesis by isolated squid giant axon provides functional evidence for localized axonal membrane protein translation.

PubMed

Mathur, Chhavi; Johnson, Kory R; Tong, Brian A; Miranda, Pablo; Srikumar, Deepa; Basilio, Daniel; Latorre, Ramon; Bezanilla, Francisco; Holmgren, Miguel

2018-02-02

Local translation of membrane proteins in neuronal subcellular domains like soma, dendrites and axon termini is well-documented. In this study, we isolated the electrical signaling unit of an axon by dissecting giant axons from mature squids (Dosidicus gigas). Axoplasm extracted from these axons was found to contain ribosomal RNAs, ~8000 messenger RNA species, many encoding the translation machinery, membrane proteins, translocon and signal recognition particle (SRP) subunits, endomembrane-associated proteins, and unprecedented proportions of SRP RNA (~68% identical to human homolog). While these components support endoplasmic reticulum-dependent protein synthesis, functional assessment of a newly synthesized membrane protein in axolemma of an isolated axon is technically challenging. Ion channels are ideal proteins for this purpose because their functional dynamics can be directly evaluated by applying voltage clamp across the axon membrane. We delivered in vitro transcribed RNA encoding native or Drosophila voltage-activated Shaker K V channel into excised squid giant axons. We found that total K + currents increased in both cases; with added inactivation kinetics on those axons injected with RNA encoding the Shaker channel. These results provide unambiguous evidence that isolated axons can exhibit de novo synthesis, assembly and membrane incorporation of fully functional oligomeric membrane proteins.

Axonal interferon responses and alphaherpesvirus neuroinvasion

NASA Astrophysics Data System (ADS)

Song, Ren

Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at a peripheral epithelial surface and continues into the peripheral nervous system (PNS) that innervates this tissue. Inflammatory responses are induced at the infected peripheral site prior to viral invasion of the PNS. PNS neurons are highly polarized cells with long axonal processes that connect to distant targets. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which include type I interferon (e.g. IFNbeta) and type II interferon (i.e. IFNgamma). IFNbeta can be produced by all types of cells, while IFNgamma is secreted by some specific types of immune cells. And both types of IFN induce antiviral responses in surrounding cells that express the IFN receptors. The fundamental question is how do PNS neurons respond to the inflammatory milieu experienced only by their axons. Axons must act as potential front-line barriers to prevent PNS infection and damage. Using compartmented cultures that physically separate neuron axons from cell bodies, I found that pretreating isolated axons with IFNbeta or IFNgamma significantly diminished the number of HSV-1 and PRV particles moving from axons to the cell bodies in an IFN receptor-dependent manner. Furthermore, I found the responses in axons are activated differentially by the two types of IFNs. The response to IFNbeta is a rapid, axon-only response, while the response to IFNgamma involves long distance signaling to the PNS cell body. For example, exposing axons to IFNbeta induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFNgamma induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated IFNgamma-, but not IFNbeta-mediated antiviral effects. Proteomic analysis of IFNbeta- or IFNgamma-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFNgamma, IFNbeta induces a non-canonical, local antiviral response in axons. The activation of a local IFNbeta response in axons represents a new paradigm for early cytokine control of neuroinvasion. And the two response modes induced by the two distinct types of IFN erect an efficient and appropriate barrier against PNS infection.

A HuD-ZBP1 ribonucleoprotein complex localizes GAP-43 mRNA into axons through its 3' untranslated region AU-rich regulatory element.

PubMed

Yoo, Soonmoon; Kim, Hak H; Kim, Paul; Donnelly, Christopher J; Kalinski, Ashley L; Vuppalanchi, Deepika; Park, Michael; Lee, Seung J; Merianda, Tanuja T; Perrone-Bizzozero, Nora I; Twiss, Jeffery L

2013-09-01

Localized translation of axonal mRNAs contributes to developmental and regenerative axon growth. Although untranslated regions (UTRs) of many different axonal mRNAs appear to drive their localization, there has been no consensus RNA structure responsible for this localization. We recently showed that limited expression of ZBP1 protein restricts axonal localization of both β-actin and GAP-43 mRNAs. β-actin 3'UTR has a defined element for interaction with ZBP1, but GAP-43 mRNA shows no homology to this RNA sequence. Here, we show that an AU-rich regulatory element (ARE) in GAP-43's 3'UTR is necessary and sufficient for its axonal localization. Axonal GAP-43 mRNA levels increase after in vivo injury, and GAP-43 mRNA shows an increased half-life in regenerating axons. GAP-43 mRNA interacts with both HuD and ZBP1, and HuD and ZBP1 co-immunoprecipitate in an RNA-dependent fashion. Reporter mRNA with the GAP-43 ARE competes with endogenous β-actin mRNA for axonal localization and decreases axon length and branching similar to the β-actin 3'UTR competing with endogenous GAP-43 mRNA. Conversely, over-expressing GAP-43 coding sequence with its 3'UTR ARE increases axonal elongation and this effect is lost when just the ARE is deleted from GAP-43's 3'UTR. We have recently found that over-expression of GAP-43 using an axonally targeted construct with the 3'UTRs of GAP-43 promoted elongating growth of axons, while restricting the mRNA to the cell body with the 3'UTR of γ-actin had minimal effect on axon length. In this study, we show that the ARE in GAP-43's 3'UTR is responsible for localization of GAP-43 mRNA into axons and is sufficient for GAP-43 protein's role in elongating axonal growth. © 2013 International Society for Neurochemistry.

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.

PubMed

Singh, Shailender; Dallenga, Tobias; Winkler, Anne; Roemer, Shanu; Maruschak, Brigitte; Siebert, Heike; Brück, Wolfgang; Stadelmann, Christine

2017-03-17

Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination. Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (Wld S ) mutant mice. The highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in Wld S mice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration did not result in a net rescue of axons in late lesion stages of experimental autoimmune encephalomyelitis. Our data indicate that in multiple sclerosis, ongoing demyelination in focal lesions is associated with axonal degeneration in the perilesional white matter, supporting a role for focal pathology in diffuse white matter damage. Also, our results suggest that interfering with Wallerian degeneration in inflammatory demyelination does not suffice to prevent acute axonal damage and finally axonal loss.

Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ.

PubMed

Zarei, Kasra; Scheetz, Todd E; Christopher, Mark; Miller, Kathy; Hedberg-Buenz, Adam; Tandon, Anamika; Anderson, Michael G; Fingert, John H; Abràmoff, Michael David

2016-05-26

We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ's performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice.

Membrane potential dynamics of axons in cultured hippocampal neurons probed by second-harmonic-generation imaging

NASA Astrophysics Data System (ADS)

Nuriya, Mutsuo; Yasui, Masato

2010-03-01

The electrical properties of axons critically influence the nature of communication between neurons. However, due to their small size, direct measurement of membrane potential dynamics in intact and complex mammalian axons has been a challenge. Furthermore, quantitative optical measurements of axonal membrane potential dynamics have not been available. To characterize the basic principles of somatic voltage signal propagation in intact axonal arbors, second-harmonic-generation (SHG) imaging is applied to cultured mouse hippocampal neurons. When FM4-64 is applied extracellularly to dissociated neurons, whole axonal arbors are visualized by SHG imaging. Upon action potential generation by somatic current injection, nonattenuating action potentials are recorded in intact axonal arbors. Interestingly, however, both current- and voltage-clamp recordings suggest that nonregenerative subthreshold somatic voltage changes at the soma are poorly conveyed to these axonal sites. These results reveal the nature of membrane potential dynamics of cultured hippocampal neurons, and further show the possibility of SHG imaging in physiological investigations of axons.

Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ

NASA Astrophysics Data System (ADS)

Zarei, Kasra; Scheetz, Todd E.; Christopher, Mark; Miller, Kathy; Hedberg-Buenz, Adam; Tandon, Anamika; Anderson, Michael G.; Fingert, John H.; Abràmoff, Michael David

2016-05-01

We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ’s performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice.

Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury.

PubMed

Liu, Shengwen; Sandner, Beatrice; Schackel, Thomas; Nicholson, LaShae; Chtarto, Abdelwahed; Tenenbaum, Liliane; Puttagunta, Radhika; Müller, Rainer; Weidner, Norbert; Blesch, Armin

2017-09-15

Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re-enter the caudal spinal cord. Recovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within and beyond the lesion site and injection of a regulatable vector for the transient expression of brain-derived neurotrophic factor (BDNF). Our data show that only with the full combination axons extend across the lesion site and that expression of BDNF beyond 4weeks does not further increase the number of regenerating axons. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Mars Pathfinder Landing Site Workshop 2: Characteristics of the Ares Vallis Region and Field Trips in the Channeled Scabland, Washington

NASA Technical Reports Server (NTRS)

Golombek, M. P. (Editor); Edgett, K. S. (Editor); Rice, J. W., Jr. (Editor)

1995-01-01

This volume, the first of two comprising the technical report for this workshop, contains papers that have been accepted for presentation at the Mars Pathfinder Landing Site Workshop 2: Characteristics of the Ares Vallis Region, September 24-30, 1995, in Spokane, Washington. The Mars Pathfinder Project received a new start in October 1993 as one of the next missions in NASA's long-term Mars exploration program. The mission involves landing a single vehicle on the surface of Mars in 1997. The project is one of the first Discovery-class missions and is required to be a quick, low-cost mission and achieve a set of significant but focused engineering, science, and technology objectives. The primary objective is to demonstrate a low-cost cruise, entry, descent, and landing system required to place a payload on the martian surface in a safe, operational configuration. Additional objectives include the deployment and operation of various science instruments and a microrover. Pathfinder paves the way for a cost-effective implementation of future Mars lander missions. Also included in this volume is the field trip guide to the Channeled Scabland and Missoula Lake Break-out. On July 4, 1997, Mars Pathfinder is scheduled to land near 19.5 deg N, 32.8 deg W, in a portion of Ares Vallis. The landing ellipse covers a huge (100 x 200 km) area that appears to include both depositional and erosional landforms created by one or more giant, catastrophic floods. One of the best known terrestrial analogs to martian outflow channels (such as Ares Vallis) is the region known as the Channeled Scabland. The field trip guide describes some of the geomorphological features of the Channeled Scabland and adjacent Lake Missoula break-out area near Lake Pend Oreille, Idaho.

Overhead View of Area Surrounding Pathfinder

NASA Technical Reports Server (NTRS)

1997-01-01

Overhead view of the area surrounding the Pathfinder lander illustrating the Sojourner traverse. Red rectangles are rover positions at the end of sols 1-30. Locations of soil mechanics experiments, wheel abrasion experiments, and APXS measurements are shown. The A numbers refer to APXS measurements as discussed in the paper by Rieder et al. (p. 1770, Science Magazine, see image note). Coordinates are given in the LL frame.

The photorealistic, interactive, three-dimensional virtual reality (VR) terrain models were created from IMP images using a software package developed for Pathfinder by C. Stoker et al. as a participating science project. By matching features in the left and right camera, an automated machine vision algorithm produced dense range maps of the nearfield, which were projected into a three-dimensional model as a connected polygonal mesh. Distance and angle measurements can be made on features viewed in the model using a mouse-driven three-dimensional cursor and a point-and-click interface. The VR model also incorporates graphical representations of the lander and rover and the sequence and spatial locations at which rover data were taken. As the rover moved, graphical models of the rover were added for each position that could be uniquely determined using stereo images of the rover taken by the IMP. Images taken by the rover were projected into the model as two-dimensional 'billboards' to show the proper perspective of these images.

NOTE: original caption as published in Science Magazine

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech).

First image of clouds over Mars

NASA Technical Reports Server (NTRS)

1997-01-01

This is the first image ever taken from the surface of Mars of an overcast sky. Featured are stratus clouds coming from the northeast at about 15 miles per hour (6.7 meters/second) at an approximate height of ten miles (16 kilometers) above the surface. The 'you are here' notation marks where Earth was situated in the sky at the time the image was taken. Scientists had hoped to see Earth in this image, but the cloudy conditions prevented a clear viewing. Similar images will be taken in the future with the hope of capturing a view of Earth. From Mars, Earth would appear as a tiny blue dot as a star would appear to an Earthbound observer. Pathfinder's imaging system will not be able to resolve Earth's moon. The clouds consist of water ice condensed on reddish dust particles suspended in the atmosphere. Clouds on Mars are sometimes localized and can sometimes cover entire regions, but have not yet been observed to cover the entire planet. The image was taken about an hour and forty minutes before sunrise by the Imager for Mars Pathfinder (IMP) on Sol 16 at about ten degrees up from the eastern Martian horizon.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages and Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Canadian Hydrogen Intensity Mapping Experiment (CHIME) pathfinder

NASA Astrophysics Data System (ADS)

Bandura, Kevin; Addison, Graeme E.; Amiri, Mandana; Bond, J. Richard; Campbell-Wilson, Duncan; Connor, Liam; Cliche, Jean-François; Davis, Greg; Deng, Meiling; Denman, Nolan; Dobbs, Matt; Fandino, Mateus; Gibbs, Kenneth; Gilbert, Adam; Halpern, Mark; Hanna, David; Hincks, Adam D.; Hinshaw, Gary; Höfer, Carolin; Klages, Peter; Landecker, Tom L.; Masui, Kiyoshi; Mena Parra, Juan; Newburgh, Laura B.; Pen, Ue-li; Peterson, Jeffrey B.; Recnik, Andre; Shaw, J. Richard; Sigurdson, Kris; Sitwell, Mike; Smecher, Graeme; Smegal, Rick; Vanderlinde, Keith; Wiebe, Don

2014-07-01

A pathfinder version of CHIME (the Canadian Hydrogen Intensity Mapping Experiment) is currently being commissioned at the Dominion Radio Astrophysical Observatory (DRAO) in Penticton, BC. The instrument is a hybrid cylindrical interferometer designed to measure the large scale neutral hydrogen power spectrum across the redshift range 0.8 to 2.5. The power spectrum will be used to measure the baryon acoustic oscillation (BAO) scale across this poorly probed redshift range where dark energy becomes a significant contributor to the evolution of the Universe. The instrument revives the cylinder design in radio astronomy with a wide field survey as a primary goal. Modern low-noise amplifiers and digital processing remove the necessity for the analog beam forming that characterized previous designs. The Pathfinder consists of two cylinders 37m long by 20m wide oriented north-south for a total collecting area of 1,500 square meters. The cylinders are stationary with no moving parts, and form a transit instrument with an instantaneous field of view of ~100 degrees by 1-2 degrees. Each CHIME Pathfinder cylinder has a feedline with 64 dual polarization feeds placed every ~30 cm which Nyquist sample the north-south sky over much of the frequency band. The signals from each dual-polarization feed are independently amplified, filtered to 400-800 MHz, and directly sampled at 800 MSps using 8 bits. The correlator is an FX design, where the Fourier transform channelization is performed in FPGAs, which are interfaced to a set of GPUs that compute the correlation matrix. The CHIME Pathfinder is a 1/10th scale prototype version of CHIME and is designed to detect the BAO feature and constrain the distance-redshift relation. The lessons learned from its implementation will be used to inform and improve the final CHIME design.

Regulation of neuronal axon specification by glia-neuron gap junctions in C. elegans.

PubMed

Meng, Lingfeng; Zhang, Albert; Jin, Yishi; Yan, Dong

2016-10-21

Axon specification is a critical step in neuronal development, and the function of glial cells in this process is not fully understood. Here, we show that C. elegans GLR glial cells regulate axon specification of their nearby GABAergic RME neurons through GLR-RME gap junctions. Disruption of GLR-RME gap junctions causes misaccumulation of axonal markers in non-axonal neurites of RME neurons and converts microtubules in those neurites to form an axon-like assembly. We further uncover that GLR-RME gap junctions regulate RME axon specification through activation of the CDK-5 pathway in a calcium-dependent manner, involving a calpain clp-4 . Therefore, our study reveals the function of glia-neuron gap junctions in neuronal axon specification and shows that calcium originated from glial cells can regulate neuronal intracellular pathways through gap junctions.

Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport

PubMed Central

Freundt, Eric C.; Maynard, Nate; Clancy, Eileen K.; Roy, Shyamali; Bousset, Luc; Sourigues, Yannick; Covert, Markus; Melki, Ronald; Kirkegaard, Karla; Brahic, Michel

2012-01-01

Objective The lesions of Parkinson's disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded α-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous α-synuclein to misfold. Here, we characterized and quantified the axonal transport of α-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport. Methods We grew primary cortical mouse neurons in microfluidic devices to separate soma from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent α-synuclein fibrils and their transfer to second-order neurons. Results Fibrillar α-synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar α-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts. Interpretation These results support the hypothesis that the progression of Parkinson's disease can be caused by neuron-to-neuron spread of α-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be transsynaptic gives hope that α-synuclein fibrils could be intercepted by drugs during the extra-cellular phase of their journey. PMID:23109146

Simulating laser interferometers for missions such as (E)Lisa, Lisa pathfinder and Grace follow-on

NASA Astrophysics Data System (ADS)

Wanner, Gudrun; Kochkina, Evgenia; Mahrdt, Christoph; Müller, Vitali; Schuster, Sönke; Heinzel, Gerhard; Danzmann, Karsten

2017-11-01

Sensing tiny distance variations interferometrically will be a key task in several future space missions. Interferometric detectors such as (e)LISA will observe gravitational waves from cosmic events such as for instance super novae and extreme mass ratio inspirals. The detection principle of such detectors is sensing phase variations due to tiny distance variations between two free floating test masses aboard two remote spacecraft originating from passing gravitational waves. This detection principle will be tested for the first time by LISA Pathfinder (launch 2015), where the interferometric readout of two free floating test masses aboard one single spacecraft will be demonstrated. Future geodesy missions will map Earths Gravity field, by interferometrically measuring distance variations between two spacecraft in low Earth orbit. This will be tested for the first time by the Laser Ranging Instrument (LRI) aboard GRACE Follow-On (launch 2017). The low noise laser interferometry of all these missions provides a number of challenging tasks. We will present optical simulations performed for the missions above. The interferometry of LISA Pathfinder is purely local (there do not exist any received beams from remote spacecraft), such that all beams can be approximated by fundamental Gaussian beams. We will present simulations regarding the coupling of residual test mass jitter (longitudinal and lateral as well as angular) to the phase readout, including Monte Carlo simulations to predict how misalignment affects resulting phase noise and estimate in-flight alignment of the test masses. In all of the mentioned missions, the local laser beams are delivered to the optical bench by fibers, resulting in laser beams in fiber modes. Besides local laser beams, the interferometry of missions such as (e)LISA and LRI involves also received beams from remote spacecraft. These beams have diameters in the range of tens of meters (LRI) or kilometers (LISA / eLISA and alike), before being clipped down to centimeter scale by the receiving aperture. The resulting top hat beams show strong diffraction effects and are therefore imaged on the optical benches. Key elements for simulations are therefore the propagation with diffraction of top hat beams and fiber modes in vacuum, as well as imaging optics causing aberration and astigmatism, with the central task to characterize the coupling of test mass or spacecraft jitter to optical readout noise, in presence of realistic alignment errors. A recurring and often limiting noise in the length measurement originates from the cross coupling of angular component jitter. This cross coupling will be briefly introduced with strategies for its mitigation in the various missions. To overcome the limitations of existing and commercial software, we have written and used for the simulations above as well as for general interferometer design purposes a dedicated software package called IfoCAD which is publicly available and will be presented as well.

Axonal Degeneration Is Mediated by the Mitochondrial Permeability Transition Pore

PubMed Central

Barrientos, Sebastian A.; Martinez, Nicolas W.; Yoo, Soonmoon; Jara, Juan S.; Zamorano, Sebastian; Hetz, Claudio; Twiss, Jeffery L.; Alvarez, Jaime; Court, Felipe A.

2011-01-01

Axonal degeneration is an active process that has been associated with neurodegenerative conditions triggered by mechanical, metabolic, infectious, toxic, hereditary and inflammatory stimuli. This degenerative process can cause permanent loss of function, so it represents a focus for neuroprotective strategies. Several signaling pathways are implicated in axonal degeneration, but identification of an integrative mechanism for this self-destructive process has remained elusive. Here, we show that rapid axonal degeneration triggered by distinct mechanical and toxic insults is dependent on the activation of the mitochondrial permeability transition pore (mPTP). Both pharmacological and genetic targeting of cyclophilin D, a functional component of the mPTP, protects severed axons and vincristine-treated neurons from axonal degeneration in ex vivo and in vitro mouse and rat model systems. These effects were observed in axons from both the peripheral and central nervous system. Our results suggest that the mPTP is a key effector of axonal degeneration, upon which several independent signaling pathways converge. Since axonal and synapse degeneration are increasingly considered early pathological events in neurodegeneration, our work identifies a potential target for therapeutic intervention in a wide variety of conditions that lead to loss of axons and subsequent functional impairment. PMID:21248121

Differential effects of Rho GTPases on axonal and dendritic development in hippocampal neurones.

PubMed

Ahnert-Hilger, G; Höltje, M; Grosse, G; Pickert, G; Mucke, C; Nixdorf-Bergweiler, B; Boquet, P; Hofmann, F; Just, I

2004-07-01

Formation of neurites and their differentiation into axons and dendrites requires precisely controlled changes in the cytoskeleton. While small GTPases of the Rho family appear to be involved in this regulation, it is still unclear how Rho function affects axonal and dendritic growth during development. Using hippocampal neurones at defined states of differentiation, we have dissected the function of RhoA in axonal and dendritic growth. Expression of a dominant negative RhoA variant inhibited axonal growth, whereas dendritic growth was promoted. The opposite phenotype was observed when a constitutively active RhoA variant was expressed. Inactivation of Rho by C3-catalysed ADP-ribosylation using C3 isoforms (Clostridium limosum, C3(lim) or Staphylococcus aureus, C3(stau2)), diminished axonal branching. By contrast, extracellularly applied nanomolar concentrations of C3 from C. botulinum (C3(bot)) or enzymatically dead C3(bot) significantly increased axon growth and axon branching. Taken together, axonal development requires activation of RhoA, whereas dendritic development benefits from its inactivation. However, extracellular application of enzymatically active or dead C3(bot) exclusively promotes axonal growth and branching suggesting a novel neurotrophic function of C3 that is independent from its enzymatic activity.

Neuronal growth cones respond to laser-induced axonal damage

PubMed Central

Wu, Tao; Mohanty, Samarendra; Gomez-Godinez, Veronica; Shi, Linda Z.; Liaw, Lih-Huei; Miotke, Jill; Meyer, Ronald L.; Berns, Michael W.

2012-01-01

Although it is well known that damage to neurons results in release of substances that inhibit axonal growth, release of chemical signals from damaged axons that attract axon growth cones has not been observed. In this study, a 532 nm 12 ns laser was focused to a diffraction-limited spot to produce site-specific damage to single goldfish axons in vitro. The axons underwent a localized decrease in thickness (‘thinning’) within seconds. Analysis by fluorescence and transmission electron microscopy indicated that there was no gross rupture of the cell membrane. Mitochondrial transport along the axonal cytoskeleton immediately stopped at the damage site, but recovered over several minutes. Within seconds of damage nearby growth cones extended filopodia towards the injury and were often observed to contact the damaged site. Turning of the growth cone towards the injured axon also was observed. Repair of the laser-induced damage was evidenced by recovery of the axon thickness as well as restoration of mitochondrial movement. We describe a new process of growth cone response to damaged axons. This has been possible through the interface of optics (laser subcellular surgery), fluorescence and electron microscopy, and a goldfish retinal ganglion cell culture model. PMID:21831892

Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration

PubMed Central

Misko, Albert; Sasaki, Yo; Tuck, Elizabeth; Milbrandt, Jeffrey; Baloh, Robert H.

2012-01-01

Summary Alterations in mitochondrial dynamics (fission, fusion and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders such as Charcot-Marie-Tooth disease, to common conditions including Alzheimer’s disease. However, the relationship between altered mitochondrial dynamics and neurodegeneration is incompletely understood. Here we show that disease associated MFN2 proteins suppressed both mitochondrial fusion and transport, and produced classic features of segmental axonal degeneration without cell body death, including neurofilament filled swellings, loss of calcium homeostasis, and accumulation of reactive oxygen species. By contrast, depletion of Opa1 suppressed mitochondrial fusion while sparing transport, and did not induce axonal degeneration. Axon degeneration induced by mutant MFN2 proteins correlated with the disruption of the proper mitochondrial positioning within axons, rather than loss of overall mitochondrial movement, or global mitochondrial dysfunction. We also found that augmenting expression of MFN1 rescued the axonal degeneration caused by MFN2 mutants, suggesting a possible therapeutic strategy for Charcot-Marie-Tooth disease. These experiments provide evidence that the ability of mitochondria to sense energy requirements and localize properly within axons is key to maintaining axonal integrity, and may be a common pathway by which disruptions in axonal transport contribute to neurodegeneration. PMID:22442078

Color Mosaic of Rover & Terrain

NASA Image and Video Library

1997-07-05

NASA's Sojourner rover and undeployed ramps onboard the Mars Pathfinder spacecraft can be seen in this image, by the Imager for Mars Pathfinder (IMP) on July 4 (Sol 1). This image has been corrected for the curvature created by parallax. The microrover Sojourner is latched to the petal, and has not yet been deployed. The ramps are a pair of deployable metal reels which will provide a track for the rover as it slowly rolls off the lander, over the spacecraft's deflated airbags, and onto the surface of Mars. Pathfinder scientists will use this image to determine whether it is safe to deploy the ramps. One or both of the ramps will be unfurled, and then scientists will decide whether the rover will use either the forward or backward ramp for its descent. http://photojournal.jpl.nasa.gov/catalog/PIA00621

Sojourner near the Rock Garden

NASA Technical Reports Server (NTRS)

1997-01-01

This image of the Sojourner rover was taken near the end of daytime operations on Sol 42. The rover is between the rocks 'Wedge' (left) and 'Flute Top' (right). Other rocks visible include 'Flat Top' (behind Flute Top) and those in the Rock Garden, at the top of the frame. The cylindrical object extending from the back end of Sojourner is the Alpha Proton X-Ray Spectrometer.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is a division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Marie Curie during ORT6

NASA Technical Reports Server (NTRS)

2003-01-01

Marie Curie sits on the lander petal prior to deployment during the pre launch Operations Readiness Test (ORT) 6.

Pathfinder, a low-cost Discovery mission, is the first of a new fleet of spacecraft that are planned to explore Mars over thenext ten years. Mars Global Surveyor, already en route, arrives at Mars on September 11 to begin a two year orbital reconnaissance of the planet's composition, topography, and climate. Additional orbiters and landers will follow every 26 months.

The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock-down

PubMed Central

Willenberg, Rafer; Zukor, Katherine; Liu, Kai; He, Zhigang; Steward, Oswald

2016-01-01

Corticospinal tract (CST) axons from one hemisphere normally extend and terminate predominantly in the contralateral spinal cord. We previously showed that deleting PTEN in the sensorimotor cortex enables CST axons to regenerate after spinal cord injury and that some regenerating axons extend along the “wrong” side. Here, we characterize the degree of specificity of regrowth in terms of laterality. PTEN was selectively deleted via cortical AAV-Cre injections in neonatal PTEN-floxed mice. As adults, mice received dorsal hemisection injuries at T12 or complete crush injuries at T9. CST axons from one hemisphere were traced by unilateral BDA injections in PTEN-deleted mice with spinal cord injury and in non-injured PTEN-floxed mice that had not received AAV-Cre. In non-injured mice, 97.9 ± 0.7% of BDA-labeled axons in white matter and 88.5 ± 1.0% of BDA-labeled axons in grey matter were contralateral to the cortex of origin. In contrast, laterality of CST axons that extended past a lesion due to PTEN deletion varied across animals. In some cases, regenerated axons extended predominantly on the ipsilateral side, in other cases, axons extended predominantly contralaterally, and in others, axons were similar in numbers on both sides. Similar results were seen in analyses of cases from previous studies using shRNA-mediated PTEN knock-down. These results indicate that CST axons that extend past a lesion due to PTEN deletion or knock-down do not maintain the contralateral rule of the non-injured CST, highlighting one aspect for how resultant circuitry from regenerating axons may differ from that of the uninjured CST. PMID:26878190

Characterizing Brain Structures and Remodeling after TBI Based on Information Content, Diffusion Entropy

PubMed Central

Fozouni, Niloufar; Chopp, Michael; Nejad-Davarani, Siamak P.; Zhang, Zheng Gang; Lehman, Norman L.; Gu, Steven; Ueno, Yuji; Lu, Mei; Ding, Guangliang; Li, Lian; Hu, Jiani; Bagher-Ebadian, Hassan; Hearshen, David; Jiang, Quan

2013-01-01

Background To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. Methods Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. Results Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. Conclusions Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease. PMID:24143186

Characterizing brain structures and remodeling after TBI based on information content, diffusion entropy.

PubMed

Fozouni, Niloufar; Chopp, Michael; Nejad-Davarani, Siamak P; Zhang, Zheng Gang; Lehman, Norman L; Gu, Steven; Ueno, Yuji; Lu, Mei; Ding, Guangliang; Li, Lian; Hu, Jiani; Bagher-Ebadian, Hassan; Hearshen, David; Jiang, Quan

2013-01-01

To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon's entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat. Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining. Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining. Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease.

Disruption of the Axonal Trafficking of Tyrosine Hydroxylase mRNA Impairs Catecholamine Biosynthesis in the Axons of Sympathetic Neurons

PubMed Central

Gioio, Anthony E.

2017-01-01

Abstract Tyrosine hydroxylase (TH) is the enzyme that catalyzes the rate-limiting step in the biosynthesis of the catecholamine neurotransmitters. In a previous communication, evidence was provided that TH mRNA is trafficked to the axon, where it is locally translated. In addition, a 50-bp sequence element in the 3′untranslated region (3’UTR) of TH mRNA was identified that directs TH mRNA to distal axons (i.e., zip-code). In the present study, the hypothesis was tested that local translation of TH plays an important role in the biosynthesis of the catecholamine neurotransmitters in the axon and/or presynaptic nerve terminal. Toward this end, a targeted deletion of the axonal transport sequence element was developed, using the lentiviral delivery of the CRISPR/Cas9 system, and two guide RNA (gRNA) sequences flanking the 50-bp cis-acting regulatory element in rat superior cervical ganglion (SCG) neurons. Deletion of the axonal transport element reduced TH mRNA levels in the distal axons and reduced the axonal protein levels of TH and TH activity as measured by phosphorylation of SER40 in SCG neurons. Moreover, deletion of the zip-code diminished the axonal levels of dopamine (DA) and norepinephrine (NE). Conversely, the local translation of exogenous TH mRNA in the distal axon enhanced TH levels and activity, and elevated axonal NE levels. Taken together, these results provide direct evidence to support the hypothesis that TH mRNA trafficking and local synthesis of TH play an important role in the synthesis of catecholamines in the axon and presynaptic terminal. PMID:28630892

A Comparative Morphometric Analysis of Three Cranial Nerves in Two Phocids: The Hooded Seal (Cystophora cristata) and the Harbor Seal (Phoca vitulina).

PubMed

Wohlert, Dennis; Kröger, Jürgen; Witt, Martin; Schmitt, Oliver; Wree, Andreas; Czech-Damal, Nicole; Siebert, Ursula; Folkow, Lars; Hanke, Frederike D

2016-03-01

While our knowledge about the senses of pinnipeds has increased over the last decades almost nothing is known about the organization of the neuroanatomical pathways. In a first approach to this field of research, we assessed the total number of myelinated axons of three cranial nerves (CNs) in the harbor (Phoca vitulina, Pv) and hooded seal (Cystophora cristata, Cc). Axons were counted in semithin sections of the nerves embedded in Epon and stained with toluidine blue. In both species, the highest axon number was found within the optic nerve (Pv 187,000 ± 8,000 axons, Cc 481,600 ± 1,300 axons). Generally, considering absolute axon numbers, far more axons were counted within the optic and trigmenial nerve (Pv 136,700 ± 2,500 axons, Cc 179,300 ± 6,900 axons) in hooded in comparison to harbor seals. The axon counts of the vestibulocochlear nerve are nearly identical for both species (Pv 87,100 ± 8,100 axons, Cc 86,600 ± 2,700 axons). However, when comparing cell density, the cell density is almost equal for all nerves for both species except for the optic nerve in which cell density was particularly higher than in the other nerves and higher in hooded in comparison to harbor seals. We here present the first comparative analysis of three CNs in two phocid seals. While the CNs of these closely related species share some general characteristics, pronounced differences in axon numbers/densities are apparent. These differences seem to reflect differences in e.g. size, habitat, and/or functional significance of the innervated sensory systems. © 2015 Wiley Periodicals, Inc.

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons.

PubMed

Gervasi, Noreen M; Scott, Shane S; Aschrafi, Armaz; Gale, Jenna; Vohra, Sanah N; MacGibeny, Margaret A; Kar, Amar N; Gioio, Anthony E; Kaplan, Barry B

2016-06-01

Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3'UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal. Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Disruption of the Axonal Trafficking of Tyrosine Hydroxylase mRNA Impairs Catecholamine Biosynthesis in the Axons of Sympathetic Neurons.

PubMed

Aschrafi, Armaz; Gioio, Anthony E; Dong, Lijin; Kaplan, Barry B

2017-01-01

Tyrosine hydroxylase (TH) is the enzyme that catalyzes the rate-limiting step in the biosynthesis of the catecholamine neurotransmitters. In a previous communication, evidence was provided that TH mRNA is trafficked to the axon, where it is locally translated. In addition, a 50-bp sequence element in the 3'untranslated region (3'UTR) of TH mRNA was identified that directs TH mRNA to distal axons (i.e., zip-code). In the present study, the hypothesis was tested that local translation of TH plays an important role in the biosynthesis of the catecholamine neurotransmitters in the axon and/or presynaptic nerve terminal. Toward this end, a targeted deletion of the axonal transport sequence element was developed, using the lentiviral delivery of the CRISPR/Cas9 system, and two guide RNA (gRNA) sequences flanking the 50-bp cis- acting regulatory element in rat superior cervical ganglion (SCG) neurons. Deletion of the axonal transport element reduced TH mRNA levels in the distal axons and reduced the axonal protein levels of TH and TH activity as measured by phosphorylation of SER40 in SCG neurons. Moreover, deletion of the zip-code diminished the axonal levels of dopamine (DA) and norepinephrine (NE). Conversely, the local translation of exogenous TH mRNA in the distal axon enhanced TH levels and activity, and elevated axonal NE levels. Taken together, these results provide direct evidence to support the hypothesis that TH mRNA trafficking and local synthesis of TH play an important role in the synthesis of catecholamines in the axon and presynaptic terminal.

R7 Photoreceptor Axon Growth Is Temporally Controlled by the Transcription Factor Ttk69, Which Inhibits Growth in Part by Promoting Transforming Growth Factor-β/Activin Signaling

PubMed Central

Kniss, Jonathan S.; Holbrook, Scott

2013-01-01

Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-β/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-β/Activin-independent mechanism. PMID:23345225

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome

PubMed Central

Fung, Lawrence K.; Quintin, Eve-Marie; Haas, Brian W.

2013-01-01

Purpose of review The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Recent findings Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive–behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well – microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Summary Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene–brain–behavior links occurring in neurodevelopmental disorders. PMID:22395002

An Unusual Splice Defect in the Mitofusin 2 Gene (MFN2) Is Associated with Degenerative Axonopathy in Tyrolean Grey Cattle

PubMed Central

Drögemüller, Cord; Reichart, Ursula; Seuberlich, Torsten; Oevermann, Anna; Baumgartner, Martin; Kühni Boghenbor, Kathrin; Stoffel, Michael H.; Syring, Claudia; Meylan, Mireille; Müller, Simone; Müller, Mathias; Gredler, Birgit

2011-01-01

Tyrolean Grey cattle represent a local breed with a population size of ∼5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in Tyrolean Grey cattle. The clinical signs of the disorder are similar to those of bovine progressive degenerative myeloencephalopathy (weaver syndrome) in Brown Swiss cattle but occur much earlier in life. The neuropathological investigation of an affected calf showed axonal degeneration in the central nervous system (CNS) and femoral nerve. The pedigrees of the affected calves suggested a monogenic autosomal recessive inheritance. We localized the responsible mutation to a 1.9 Mb interval on chromosome 16 by genome-wide association and haplotype mapping. The MFN2 gene located in this interval encodes mitofusin 2, a mitochondrial membrane protein. A heritable human axonal neuropathy, Charcot-Marie-Tooth disease-2A2 (CMT2A2), is caused by MFN2 mutations. Therefore, we considered MFN2 a positional and functional candidate gene and performed mutation analysis in affected and control Tyrolean Grey cattle. We did not find any non-synonymous variants. However, we identified a perfectly associated silent SNP in the coding region of exon 20 of the MFN2 gene. This SNP is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron. This splicing defect represents a potential explanation for the observed degenerative axonopathy. Marker assisted selection can now be used to eliminate degenerative axonopathy from Tyrolean Grey cattle. PMID:21526202

An unusual splice defect in the mitofusin 2 gene (MFN2) is associated with degenerative axonopathy in Tyrolean Grey cattle.

PubMed

Drögemüller, Cord; Reichart, Ursula; Seuberlich, Torsten; Oevermann, Anna; Baumgartner, Martin; Kühni Boghenbor, Kathrin; Stoffel, Michael H; Syring, Claudia; Meylan, Mireille; Müller, Simone; Müller, Mathias; Gredler, Birgit; Sölkner, Johann; Leeb, Tosso

2011-04-15

Tyrolean Grey cattle represent a local breed with a population size of ∼5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in Tyrolean Grey cattle. The clinical signs of the disorder are similar to those of bovine progressive degenerative myeloencephalopathy (weaver syndrome) in Brown Swiss cattle but occur much earlier in life. The neuropathological investigation of an affected calf showed axonal degeneration in the central nervous system (CNS) and femoral nerve. The pedigrees of the affected calves suggested a monogenic autosomal recessive inheritance. We localized the responsible mutation to a 1.9 Mb interval on chromosome 16 by genome-wide association and haplotype mapping. The MFN2 gene located in this interval encodes mitofusin 2, a mitochondrial membrane protein. A heritable human axonal neuropathy, Charcot-Marie-Tooth disease-2A2 (CMT2A2), is caused by MFN2 mutations. Therefore, we considered MFN2 a positional and functional candidate gene and performed mutation analysis in affected and control Tyrolean Grey cattle. We did not find any non-synonymous variants. However, we identified a perfectly associated silent SNP in the coding region of exon 20 of the MFN2 gene. This SNP is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron. This splicing defect represents a potential explanation for the observed degenerative axonopathy. Marker assisted selection can now be used to eliminate degenerative axonopathy from Tyrolean Grey cattle.

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

PubMed Central

Chung, Peter J.; Choi, Myung Chul; Miller, Herbert P.; Feinstein, H. Eric; Raviv, Uri; Li, Youli; Wilson, Leslie; Feinstein, Stuart C.; Safinya, Cyrus R.

2015-01-01

Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer’s. Here, we report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (P). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; ΦTau = 1/10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to PB ∼ 10,000–20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (PB ∼ 1,000–2,000 Pa) over the same range. Remarkably, the abrupt increase in PB observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < ΦTau < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT–MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment. PMID:26542680

Epilepsy following cortical injury: Cellular and molecular mechanisms as targets for potential prophylaxis

PubMed Central

Prince, David A.; Parada, Isabel; Scalise, Karina; Graber, Kevin; Shen, Fran

2009-01-01

Summary The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential “prime movers”: disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical (“undercut”) model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans are critical and need to be resolved. PMID:19187292

Identification of GLI Mutations in Patients With Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice.

PubMed

Liu, Jessica Ai-Jia; Lai, Frank Pui-Ling; Gui, Hong-Sheng; Sham, Mai-Har; Tam, Paul Kwong-Hang; Garcia-Barcelo, Maria-Mercedes; Hui, Chi-Chung; Ngan, Elly Sau-Wai

2015-12-01

Hirschsprung disease is characterized by a deficit in enteric neurons, which are derived from neural crest cells (NCCs). Aberrant hedgehog signaling disrupts NCC differentiation and might cause Hirschsprung disease. We performed genetic analyses to determine whether hedgehog signaling is involved in pathogenesis. We performed deep-target sequencing of DNA from 20 patients with Hirschsprung disease (16 men, 4 women), and 20 individuals without (controls), and searched for mutation(s) in GLI1, GLI2, GLI3, SUFU, and SOX10. Biological effects of GLI mutations were tested in luciferase reporter assays using HeLa or neuroblastoma cell lines. Development of the enteric nervous system was studied in Sufu(f/f), Gli3(Δ699), Wnt1-Cre, and Sox10(NGFP) mice using immunohistochemical and whole-mount staining procedures to quantify enteric neurons and glia and analyze axon fasciculation, respectively. NCC migration was studied using time-lapse imaging. We identified 3 mutations in GLI in 5 patients with Hirschsprung disease but no controls; all lead to increased transcription of SOX10 in cell lines. SUFU, GLI, and SOX10 form a regulatory loop that controls the neuronal vs glial lineages and migration of NCCs. Sufu mutants mice had high Gli activity, due to loss of Sufu, disrupting the regulatory loop and migration of enteric NCCs, leading to defective axonal fasciculation, delayed gut colonization, or intestinal hypoganglionosis. The ratio of enteric neurons to glia correlated inversely with Gli activity. We identified mutations that increase GLI activity in patients with Hirschsprung disease. Disruption of the SUFU-GLI-SOX10 regulatory loop disrupts migration of NCCs and development of the enteric nervous system in mice. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

A Novel Approach for Studying the Physiology and Pathophysiology of Myelinated and Non-Myelinated Axons in the CNS White Matter.

PubMed

Li, Lijun; Velumian, Alexander A; Samoilova, Marina; Fehlings, Michael G

2016-01-01

Advances in brain connectomics set the need for detailed knowledge of functional properties of myelinated and non-myelinated (if present) axons in specific white matter pathways. The corpus callosum (CC), a major white matter structure interconnecting brain hemispheres, is extensively used for studying CNS axonal function. Unlike another widely used CNS white matter preparation, the optic nerve where all axons are myelinated, the CC contains also a large population of non-myelinated axons, making it particularly useful for studying both types of axons. Electrophysiological studies of optic nerve use suction electrodes on nerve ends to stimulate and record compound action potentials (CAPs) that adequately represent its axonal population, whereas CC studies use microelectrodes (MEs), recording from a limited area within the CC. Here we introduce a novel robust isolated "whole" CC preparation comparable to optic nerve. Unlike ME recordings where the CC CAP peaks representing myelinated and non-myelinated axons vary broadly in size, "whole" CC CAPs show stable reproducible ratios of these two main peaks, and also reveal a third peak, suggesting a distinct group of smaller caliber non-myelinated axons. We provide detailed characterization of "whole" CC CAPs and conduction velocities of myelinated and non-myelinated axons along the rostro-caudal axis of CC body and show advantages of this preparation for comparing axonal function in wild type and dysmyelinated shiverer mice, studying the effects of temperature dependence, bath-applied drugs and ischemia modeled by oxygen-glucose deprivation. Due to the isolation from gray matter, our approach allows for studying CC axonal function without possible "contamination" by reverberating signals from gray matter. Our analysis of "whole" CC CAPs revealed higher complexity of myelinated and non-myelinated axonal populations, not noticed earlier. This preparation may have a broad range of applications as a robust model for studying myelinated and non-myelinated axons of the CNS in various experimental models.

A Novel Approach for Studying the Physiology and Pathophysiology of Myelinated and Non-Myelinated Axons in the CNS White Matter

PubMed Central

Samoilova, Marina

2016-01-01

Advances in brain connectomics set the need for detailed knowledge of functional properties of myelinated and non-myelinated (if present) axons in specific white matter pathways. The corpus callosum (CC), a major white matter structure interconnecting brain hemispheres, is extensively used for studying CNS axonal function. Unlike another widely used CNS white matter preparation, the optic nerve where all axons are myelinated, the CC contains also a large population of non-myelinated axons, making it particularly useful for studying both types of axons. Electrophysiological studies of optic nerve use suction electrodes on nerve ends to stimulate and record compound action potentials (CAPs) that adequately represent its axonal population, whereas CC studies use microelectrodes (MEs), recording from a limited area within the CC. Here we introduce a novel robust isolated "whole" CC preparation comparable to optic nerve. Unlike ME recordings where the CC CAP peaks representing myelinated and non-myelinated axons vary broadly in size, "whole" CC CAPs show stable reproducible ratios of these two main peaks, and also reveal a third peak, suggesting a distinct group of smaller caliber non-myelinated axons. We provide detailed characterization of "whole" CC CAPs and conduction velocities of myelinated and non-myelinated axons along the rostro-caudal axis of CC body and show advantages of this preparation for comparing axonal function in wild type and dysmyelinated shiverer mice, studying the effects of temperature dependence, bath-applied drugs and ischemia modeled by oxygen-glucose deprivation. Due to the isolation from gray matter, our approach allows for studying CC axonal function without possible "contamination" by reverberating signals from gray matter. Our analysis of "whole" CC CAPs revealed higher complexity of myelinated and non-myelinated axonal populations, not noticed earlier. This preparation may have a broad range of applications as a robust model for studying myelinated and non-myelinated axons of the CNS in various experimental models. PMID:27829055

Sodium Channel β2 Subunits Prevent Action Potential Propagation Failures at Axonal Branch Points.

PubMed

Cho, In Ha; Panzera, Lauren C; Chin, Morven; Hoppa, Michael B

2017-09-27

Neurotransmitter release depends on voltage-gated Na + channels (Na v s) to propagate an action potential (AP) successfully from the axon hillock to a synaptic terminal. Unmyelinated sections of axon are very diverse structures encompassing branch points and numerous presynaptic terminals with undefined molecular partners of Na + channels. Using optical recordings of Ca 2+ and membrane voltage, we demonstrate here that Na + channel β2 subunits (Na v β2s) are required to prevent AP propagation failures across the axonal arborization of cultured rat hippocampal neurons (mixed male and female). When Na v β2 expression was reduced, we identified two specific phenotypes: (1) membrane excitability and AP-evoked Ca 2+ entry were impaired at synapses and (2) AP propagation was severely compromised with >40% of axonal branches no longer responding to AP-stimulation. We went on to show that a great deal of electrical signaling heterogeneity exists in AP waveforms across the axonal arborization independent of axon morphology. Therefore, Na v β2 is a critical regulator of axonal excitability and synaptic function in unmyelinated axons. SIGNIFICANCE STATEMENT Voltage-gated Ca 2+ channels are fulcrums of neurotransmission that convert electrical inputs into chemical outputs in the form of vesicle fusion at synaptic terminals. However, the role of the electrical signal, the presynaptic action potential (AP), in modulating synaptic transmission is less clear. What is the fidelity of a propagating AP waveform in the axon and what molecules shape it throughout the axonal arborization? Our work identifies several new features of AP propagation in unmyelinated axons: (1) branches of a single axonal arborization have variable AP waveforms independent of morphology, (2) Na + channel β2 subunits modulate AP-evoked Ca 2+ -influx, and (3) β2 subunits maintain successful AP propagation across the axonal arbor. These findings are relevant to understanding the flow of excitation in the brain. Copyright © 2017 the authors 0270-6474/17/379519-15$15.00/0.

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy.

PubMed

Jelescu, Ileana O; Zurek, Magdalena; Winters, Kerryanne V; Veraart, Jelle; Rajaratnam, Anjali; Kim, Nathanael S; Babb, James S; Shepherd, Timothy M; Novikov, Dmitry S; Kim, Sungheon G; Fieremans, Els

2016-05-15

There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6weeks) and chronic (12weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p<0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p=0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ=0.66; p=0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ=0.48; p=0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter. Copyright © 2016 Elsevier Inc. All rights reserved.

Two different immunostaining patterns of beta-amyloid precursor protein (APP) may distinguish traumatic from nontraumatic axonal injury.

PubMed

Hayashi, Takahito; Ago, Kazutoshi; Nakamae, Takuma; Higo, Eri; Ogata, Mamoru

2015-09-01

Immunostaining for beta-amyloid precursor protein (APP) is recognized as an effective tool for detecting traumatic axonal injury, but it also detects axonal injury due to ischemic or other metabolic causes. Previously, we reported two different patterns of APP staining: labeled axons oriented along with white matter bundles (pattern 1) and labeled axons scattered irregularly (pattern 2) (Hayashi et al. (Leg Med (Tokyo) 11:S171-173, 2009). In this study, we investigated whether these two patterns are consistent with patterns of trauma and hypoxic brain damage, respectively. Sections of the corpus callosum from 44 cases of blunt head injury and equivalent control tissue were immunostained for APP. APP was detected in injured axons such as axonal bulbs and varicose axons in 24 of the 44 cases of head injuries that also survived for three or more hours after injury. In 21 of the 24 APP-positive cases, pattern 1 alone was observed in 14 cases, pattern 2 alone was not observed in any cases, and both patterns 1 and 2 were detected in 7 cases. APP-labeled injured axons were detected in 3 of the 44 control cases, all of which were pattern 2. These results suggest that pattern 1 indicates traumatic axonal injury, while pattern 2 results from hypoxic insult. These patterns may be useful to differentiate between traumatic and nontraumatic axonal injuries.

DSMC Simulations of Blunt Body Flows for Mars Entries: Mars Pathfinder and Mars Microprobe Capsules

NASA Technical Reports Server (NTRS)

Moss, James N.; Wilmoth, Richard G.; Price, Joseph M.

1997-01-01

The hypersonic transitional flow aerodynamics of the Mars Pathfinder and Mars Microprobe capsules are simulated with the direct simulation Monte Carlo method. Calculations of axial, normal, and static pitching coefficients were obtained over an angle of attack range comparable to actual flight requirements. Comparisons are made with modified Newtonian and free-molecular-flow calculations. Aerothermal results were also obtained for zero incidence entry conditions.

Measuring Pilot Knowledge in Training: The Pathfinder Network Scaling Technique

DTIC Science & Technology

2007-01-01

Network Scaling Technique Leah J. Rowe Roger W. Schvaneveldt L -3 Communications Arizona State University Mesa, AZ Mesa, AZ leah.rowe...7293 Page 2 of 8 Measuring Pilot Knowledge in Training: The Pathfinder Network Scaling Technique Leah J. Rowe Roger W. Schvaneveldt L -3...training. ABOUT THE AUTHORS Leah J. Rowe is a Training Research Specialist with L -3 Communications at the Air Force Research Laboratory

Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner.

PubMed

Mitew, Stanislaw; Gobius, Ilan; Fenlon, Laura R; McDougall, Stuart J; Hawkes, David; Xing, Yao Lulu; Bujalka, Helena; Gundlach, Andrew L; Richards, Linda J; Kilpatrick, Trevor J; Merson, Tobias D; Emery, Ben

2018-01-22

Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the individual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of individual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS.

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development.

PubMed

Kaplan, Andrew; Bueno, Mardja; Hua, Luyang; Fournier, Alyson E

2018-01-01

The failure of damaged axons to regrow underlies disability in central nervous system injury and disease. Therapies that stimulate axon repair will be critical to restore function. Extensive axon regeneration can be induced by manipulation of oncogenes and tumor suppressors; however, it has been difficult to translate this into functional recovery in models of spinal cord injury. The current challenge is to maximize the functional integration of regenerating axons to recover motor and sensory behaviors. Insights into axonal growth and wiring during nervous system development are helping guide new approaches to boost regeneration and functional connectivity after injury in the mature nervous system. Here we discuss our current understanding of axonal behavior after injury and prospects for the development of drugs to optimize axon regeneration and functional recovery after CNS injury. Developmental Dynamics 247:18-23, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Molecular, Cellular and Functional Events in Axonal Sprouting after Stroke

PubMed Central

Kathirvelu, Balachander; Schweppe, Catherine A; Nie, Esther H

2016-01-01

Stroke is the leading cause of adult disability. Yet there is a limited degree of recovery in this disease. One of the mechanisms of recovery is the formation of new connections in the brain and spinal cord after stroke: post-stroke axonal sprouting. Studies indicate that post-stroke axonal sprouting occurs in mice, rats, primates and humans. Inducing post-stroke axonal sprouting in specific connections enhances recovery; blocking axonal sprouting impairs recovery. Behavioral activity patterns after stroke modify the axonal sprouting response. A unique regenerative molecular program mediates this aspect of tissue repair in the CNS. The types of connections that are formed after stroke indicate three patterns of axonal sprouting after stroke: Reactive, Reparative and Unbounded Axonal Sprouting. These differ in mechanism, location, relationship to behavioral recovery and, importantly, in their prospect for therapeutic manipulation to enhance tissue repair. PMID:26874223

Visualization of Motor Axon Navigation and Quantification of Axon Arborization In Mouse Embryos Using Light Sheet Fluorescence Microscopy.

PubMed

Liau, Ee Shan; Yen, Ya-Ping; Chen, Jun-An

2018-05-11

Spinal motor neurons (MNs) extend their axons to communicate with their innervating targets, thereby controlling movement and complex tasks in vertebrates. Thus, it is critical to uncover the molecular mechanisms of how motor axons navigate to, arborize, and innervate their peripheral muscle targets during development and degeneration. Although transgenic Hb9::GFP mouse lines have long served to visualize motor axon trajectories during embryonic development, detailed descriptions of the full spectrum of axon terminal arborization remain incomplete due to the pattern complexity and limitations of current optical microscopy. Here, we describe an improved protocol that combines light sheet fluorescence microscopy (LSFM) and robust image analysis to qualitatively and quantitatively visualize developing motor axons. This system can be easily adopted to cross genetic mutants or MN disease models with Hb9::GFP lines, revealing novel molecular mechanisms that lead to defects in motor axon navigation and arborization.

Identifying motor and sensory myelinated axons in rabbit peripheral nerves by histochemical staining for carbonic anhydrase and cholinesterase activities

NASA Technical Reports Server (NTRS)

Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.

1988-01-01

Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.

Contribution of cytoskeletal elements to the axonal mechanical properties

PubMed Central

2013-01-01

Background Microtubules, microfilaments, and neurofilaments are cytoskeletal elements that affect cell morphology, cellular processes, and mechanical structures in neural cells. The objective of the current study was to investigate the contribution of each type of cytoskeletal element to the mechanical properties of axons of dorsal root and sympathetic ganglia cells in chick embryos. Results Microtubules, microfilaments, and neurofilaments in axons were disrupted by nocodazole, cytochalasin D, and acrylamide, respectively, or a combination of the three. An atomic force microscope (AFM) was then used to compress the treated axons, and the resulting corresponding force-deformation information was analyzed to estimate the mechanical properties of axons that were partially or fully disrupted. Conclusion We have found that the mechanical stiffness was most reduced in microtubules-disrupted-axons, followed by neurofilaments-disrupted- and microfilaments-disrupted-axons. This suggests that microtubules contribute the most of the mechanical stiffness to axons. PMID:24007256

Reconsidering the Theological and Ethical Implications of Extraterrestrial Life

NASA Technical Reports Server (NTRS)

Randolph, Richard O. (Editor); Race, Margaret S.; McKay, Christopher P. (Editor)

1997-01-01

As we stand on the threshold of a new millennium, we also find ourselves at the brink of a new and exciting era in space exploration. In fact, this new era has already begun, with the successful landing and exploration of Mars by the Pathfinder mission in July 1997. Pathfinder represents an important scientific accomplishment for NASA because it demonstrated the agency's ability to successfully explore space at a relatively modest price. At the same time, Pathfinder revealed once again the genuine interest and fascination that people all over planet Earth have for space exploration. The Pathfinder mission is just one of several recent events-both scientific and cultural-that reveal this deep and almost unquenchable curiosity about space-and the possibility that there is life "out there." In August 1996, the public was captivated with NASA's announcement that a meteorite from Mars may contain evidence of early microscopic life. Shortly after the NASA announcement, media coverage of the discovery-and public discourse concerning the discovery-turned to an examination of the theological implications of evidence for extraterrestrial, albeit unintelligent, life. To a lesser extent, public reaction to the Hale-Bopp comet in the Spring of 1996 is also suggestive of many persons' deep passion to know more about space.

North Twin Peak in super resolution

NASA Technical Reports Server (NTRS)

1997-01-01

This pair of images shows the result of taking a sequence of 25 identical exposures from the Imager for Mars Pathfinder (IMP) of the northern Twin Peak, with small camera motions, and processing them with the Super-Resolution algorithm developed at NASA's Ames Research Center.

The upper image is a representative input image, scaled up by a factor of five, with the pixel edges smoothed out for a fair comparison. The lower image allows significantly finer detail to be resolved.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

The super-resolution research was conducted by Peter Cheeseman, Bob Kanefsky, Robin Hanson, and John Stutz of NASA's Ames Research Center, Mountain View, CA. More information on this technology is available on the Ames Super Resolution home page at

http://ic-www.arc.nasa.gov/ic/projects/bayes-group/ group/super-res/

Optic nerve regeneration in the mouse is a complex trait modulated by genetic background

PubMed Central

Wang, Jiaxing; Li, Ying; King, Rebecca; Struebing, Felix L.

2018-01-01

Purpose The present study is designed to identify the influences of genetic background on optic nerve regeneration using the two parental strains (C57BL/6J and DBA/2J) and seven BXD recombinant inbred mouse strains. Methods To study regeneration in the optic nerve, Pten was knocked down in the retinal ganglion cells using adenoassociated virus (AAV) delivery of shRNA, and a mild inflammatory response was induced with an intravitreal injection of zymosan with CPT-cAMP. The axons of the retinal ganglion cells were damaged by optic nerve crush (ONC). Following a 12-day survival period, regenerating axons were labeled by cholera toxin B, and 2 days later, the regenerating axons within the optic nerve were examined. The number of axons at 0.5 mm and 1 mm from the crush site were counted. In addition, we measured the distance that five axons had grown down the nerve and the longest distance a single axon reached. Results The analysis revealed a considerable amount of differential axonal regeneration across the seven BXD strains and the parental strains. There was a statistically significant difference (p=0.014 Mann–Whitney U test) in the regenerative capacity in the number of axons reaching 0.5 mm from a low of 236.1±24.4 axons in the BXD102 mice to a high of 759.8±79.2 axons in the BXD29 mice. There were also statistically significant differences (p=0.014 Mann–Whitney U test) in the distance axons traveled. Looking at a minimum of five axons, the shortest distance was 787.2±46.5 µm in the BXD102 mice, and the maximum distance was 2025.5±223.3 µm in the BXD29 mice. Conclusions Differences in genetic background can have a profound effect on axonal regeneration causing a threefold increase in the number of regenerating axons at 0.5 mm from the crush site and a 2.5-fold increase in the distance traveled by at least five axons in the damaged optic nerve. PMID:29463955

The L1-type cell adhesion molecule Neuroglian is necessary for maintenance of sensory axon advance in the Drosophila embryo.

PubMed

Martin, Veronica; Mrkusich, Eli; Steinel, Martin C; Rice, Jason; Merritt, David J; Whitington, Paul M

2008-04-08

Cell adhesion molecules have long been implicated in the regulation of axon growth, but the precise cellular roles played by individual cell adhesion molecules and the molecular basis for their action are still not well understood. We have used the sensory system of the Drosophila embryo to shed light on the mechanism by which the L1-type cell adhesion molecule Neuroglian regulates axon growth. We have found a highly penetrant sensory axon stalling phenotype in neuroglian mutant embryos. Axons stalled at a variety of positions along their normal trajectory, but most commonly in the periphery some distance along the peripheral nerve. All lateral and dorsal cluster sensory neurons examined, except for the dorsal cluster neuron dbd, showed stalling. Sensory axons were never seen to project along inappropriate pathways in neuroglian mutants and stalled axons showed normal patterns of fasciculation within nerves. The growth cones of stalled axons possessed a simple morphology, similar to their appearance in wild-type embryos when advancing along nerves. Driving expression of the wild-type form of Neuroglian in sensory neurons alone rescued the neuroglian mutant phenotype of both pioneering and follower neurons. A partial rescue was achieved by expressing the Neuroglian extracellular domain. Over/mis-expression of Neuroglian in all neurons, oenocytes or trachea had no apparent effect on sensory axon growth. We conclude that Neuroglian is necessary to maintain axon advance along axonal substrates, but is not required for initiation of axon outgrowth, axon fasciculation or recognition of correct growth substrates. Expression of Neuroglian in sensory neurons alone is sufficient to promote axon advance and the intracellular region of the molecule is largely dispensable for this function. It is unlikely, therefore, that Nrg acts as a molecular 'clutch' to couple adhesion of F-actin within the growth cone to the extracellular substrate. Rather, we suggest that Neuroglian mediates sensory axon advance by promoting adhesion of the surface of the growth cone to its substrate. Our finding that stalling of a pioneer sensory neuron is rescued by driving Neuroglian in sensory neurons alone may suggest that Neuroglian can act in a heterophilic fashion.

Heterogeneity of the Axon Initial Segment in Interneurons and Pyramidal Cells of Rodent Visual Cortex

PubMed Central

Höfflin, Felix; Jack, Alexander; Riedel, Christian; Mack-Bucher, Julia; Roos, Johannes; Corcelli, Corinna; Schultz, Christian; Wahle, Petra; Engelhardt, Maren

2017-01-01

The microdomain that orchestrates action potential initiation in neurons is the axon initial segment (AIS). It has long been considered to be a rather homogeneous domain at the very proximal axon hillock with relatively stable length, particularly in cortical pyramidal cells. However, studies in other brain regions paint a different picture. In hippocampal CA1, up to 50% of axons emerge from basal dendrites. Further, in about 30% of thick-tufted layer V pyramidal neurons in rat somatosensory cortex, axons have a dendritic origin. Consequently, the AIS is separated from the soma. Recent in vitro and in vivo studies have shown that cellular excitability is a function of AIS length/position and somatodendritic morphology, undermining a potentially significant impact of AIS heterogeneity for neuronal function. We therefore investigated neocortical axon morphology and AIS composition, hypothesizing that the initial observation of seemingly homogeneous AIS is inadequate and needs to take into account neuronal cell types. Here, we biolistically transfected cortical neurons in organotypic cultures to visualize the entire neuron and classify cell types in combination with immunolabeling against AIS markers. Using confocal microscopy and morphometric analysis, we investigated axon origin, AIS position, length, diameter as well as distance to the soma. We find a substantial AIS heterogeneity in visual cortical neurons, classified into three groups: (I) axons with somatic origin with proximal AIS at the axon hillock; (II) axons with somatic origin with distal AIS, with a discernible gap between the AIS and the soma; and (III) axons with dendritic origin (axon-carrying dendrite cell, AcD cell) and an AIS either starting directly at the axon origin or more distal to that point. Pyramidal cells have significantly longer AIS than interneurons. Interneurons with vertical columnar axonal projections have significantly more distal AIS locations than all other cells with their prevailing phenotype as an AcD cell. In contrast, neurons with perisomatic terminations display most often an axon originating from the soma. Our data contribute to the emerging understanding that AIS morphology is highly variable, and potentially a function of the cell type. PMID:29170630

The L1-type cell adhesion molecule Neuroglian is necessary for maintenance of sensory axon advance in the Drosophila embryo

PubMed Central

Martin, Veronica; Mrkusich, Eli; Steinel, Martin C; Rice, Jason; Merritt, David J; Whitington, Paul M

2008-01-01

Background Cell adhesion molecules have long been implicated in the regulation of axon growth, but the precise cellular roles played by individual cell adhesion molecules and the molecular basis for their action are still not well understood. We have used the sensory system of the Drosophila embryo to shed light on the mechanism by which the L1-type cell adhesion molecule Neuroglian regulates axon growth. Results We have found a highly penetrant sensory axon stalling phenotype in neuroglian mutant embryos. Axons stalled at a variety of positions along their normal trajectory, but most commonly in the periphery some distance along the peripheral nerve. All lateral and dorsal cluster sensory neurons examined, except for the dorsal cluster neuron dbd, showed stalling. Sensory axons were never seen to project along inappropriate pathways in neuroglian mutants and stalled axons showed normal patterns of fasciculation within nerves. The growth cones of stalled axons possessed a simple morphology, similar to their appearance in wild-type embryos when advancing along nerves. Driving expression of the wild-type form of Neuroglian in sensory neurons alone rescued the neuroglian mutant phenotype of both pioneering and follower neurons. A partial rescue was achieved by expressing the Neuroglian extracellular domain. Over/mis-expression of Neuroglian in all neurons, oenocytes or trachea had no apparent effect on sensory axon growth. Conclusion We conclude that Neuroglian is necessary to maintain axon advance along axonal substrates, but is not required for initiation of axon outgrowth, axon fasciculation or recognition of correct growth substrates. Expression of Neuroglian in sensory neurons alone is sufficient to promote axon advance and the intracellular region of the molecule is largely dispensable for this function. It is unlikely, therefore, that Nrg acts as a molecular 'clutch' to couple adhesion of F-actin within the growth cone to the extracellular substrate. Rather, we suggest that Neuroglian mediates sensory axon advance by promoting adhesion of the surface of the growth cone to its substrate. Our finding that stalling of a pioneer sensory neuron is rescued by driving Neuroglian in sensory neurons alone may suggest that Neuroglian can act in a heterophilic fashion. PMID:18397531

C. elegans dystroglycan coordinates responsiveness of follower axons to dorsal/ventral and anterior/posterior guidance cues

PubMed Central

Johnson, Robert P.; Kramer, James M.

2012-01-01

Neural development in metazoans is characterized by the establishment of initial process tracts by pioneer axons and the subsequent extension of follower axons along these pioneer processes. Mechanisms governing the fidelity of follower extension along pioneered routes are largely unknown. In C. elegans, formation of the right angle-shaped lumbar commissure connecting the lumbar and preanal ganglia is an example of pioneer/follower dynamics. We find that the dystroglycan ortholog DGN-1 mediates the fidelity of follower lumbar commissure axon extension along the pioneer axon route. In dgn-1 mutants, the axon of the pioneer PVQ neuron faithfully establishes the lumbar commissure, but axons of follower lumbar neurons, such as PVC, frequently bypass the lumbar commissure and extend along an oblique trajectory directly toward the preanal ganglion. In contrast, disruption of the UNC-6/netrin guidance pathway principally perturbs PVQ ventral guidance to pioneer the lumbar commissure. Loss of DGN-1 in unc-6 mutants has a quantitatively similar effect on follower axon guidance regardless of PVQ axon route, indicating that DGN-1 does not mediate follower/pioneer adhesion. Instead, DGN-1 appears to block premature responsiveness of follower axons to a preanal ganglion-directed guidance cue which mediates ventral-to-anterior reorientation of lumbar commissure axons. Deletion analysis shows that only the most N-terminal DGN-1 domain is required for these activities. These studies suggest that dystroglycan modulation of growth cone responsiveness to conflicting guidance cues is important for restricting follower axon extension to the tracts laid down by pioneers. PMID:22275151

The corpus callosum in primates: processing speed of axons and the evolution of hemispheric asymmetry

PubMed Central

Phillips, Kimberley A.; Stimpson, Cheryl D.; Smaers, Jeroen B.; Raghanti, Mary Ann; Jacobs, Bob; Popratiloff, Anastas; Hof, Patrick R.; Sherwood, Chet C.

2015-01-01

Interhemispheric communication may be constrained as brain size increases because of transmission delays in action potentials over the length of axons. Although one might expect larger brains to have progressively thicker axons to compensate, spatial packing is a limiting factor. Axon size distributions within the primate corpus callosum (CC) may provide insights into how these demands affect conduction velocity. We used electron microscopy to explore phylogenetic variation in myelinated axon density and diameter of the CC from 14 different anthropoid primate species, including humans. The majority of axons were less than 1 µm in diameter across all species, indicating that conduction velocity for most interhemispheric communication is relatively constant regardless of brain size. The largest axons within the upper 95th percentile scaled with a progressively higher exponent than the median axons towards the posterior region of the CC. While brain mass among the primates in our analysis varied by 97-fold, estimates of the fastest cross-brain conduction times, as conveyed by axons at the 95th percentile, varied within a relatively narrow range between 3 and 9 ms across species, whereas cross-brain conduction times for the median axon diameters differed more substantially between 11 and 38 ms. Nonetheless, for both size classes of axons, an increase in diameter does not entirely compensate for the delay in interhemispheric transmission time that accompanies larger brain size. Such biophysical constraints on the processing speed of axons conveyed by the CC may play an important role in the evolution of hemispheric asymmetry. PMID:26511047

Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons.

PubMed

Gamage, Kanchana K; Cheng, Irene; Park, Rachel E; Karim, Mardeen S; Edamura, Kazusa; Hughes, Christopher; Spano, Anthony J; Erisir, Alev; Deppmann, Christopher D

2017-03-20

Axon degeneration during development is required to sculpt a functional nervous system and is also a hallmark of pathological insult, such as injury [1, 2]. Despite similar morphological characteristics, very little overlap in molecular mechanisms has been reported between pathological and developmental degeneration [3-5]. In the peripheral nervous system (PNS), developmental axon pruning relies on receptor-mediated extrinsic degeneration mechanisms to determine which axons are maintained or degenerated [5-7]. Receptors have not been implicated in Wallerian axon degeneration; instead, axon autonomous, intrinsic mechanisms are thought to be the primary driver for this type of axon disintegration [8-10]. Here we survey the role of neuronally expressed, paralogous tumor necrosis factor receptor super family (TNFRSF) members in Wallerian degeneration. We find that an orphan receptor, death receptor 6 (DR6), is required to drive axon degeneration after axotomy in sympathetic and sensory neurons cultured in microfluidic devices. We sought to validate these in vitro findings in vivo using a transected sciatic nerve model. Consistent with the in vitro findings, DR6 -/- animals displayed preserved axons up to 4 weeks after injury. In contrast to phenotypes observed in Wld s and Sarm1 -/- mice, preserved axons in DR6 -/- animals display profound myelin remodeling. This indicates that deterioration of axons and myelin after axotomy are mechanistically distinct processes. Finally, we find that JNK signaling after injury requires DR6, suggesting a link between this novel extrinsic pathway and the axon autonomous, intrinsic pathways that have become established for Wallerian degeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Can injured adult CNS axons regenerate by recapitulating development?

PubMed

Hilton, Brett J; Bradke, Frank

2017-10-01

In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS. © 2017. Published by The Company of Biologists Ltd.

L1CAM/Neuroglian controls the axon–axon interactions establishing layered and lobular mushroom body architecture

PubMed Central

Siegenthaler, Dominique; Enneking, Eva-Maria; Moreno, Eliza

2015-01-01

The establishment of neuronal circuits depends on the guidance of axons both along and in between axonal populations of different identity; however, the molecular principles controlling axon–axon interactions in vivo remain largely elusive. We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory. We addressed the regulatory mechanisms controlling homophilic Neuroglian-mediated cell adhesion by analyzing targeted mutations of extra- and intracellular Neuroglian domains in combination with cell type–specific rescue assays in vivo. We demonstrate independent and cooperative domain requirements: intercalating growth depends on homophilic adhesion mediated by extracellular Ig domains. For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations. Together, our results provide novel mechanistic insights into cell adhesion molecule–mediated axon–axon interactions that enable precise assembly of complex neuronal circuits. PMID:25825519

Functional ionotropic glutamate receptors on peripheral axons and myelin.

PubMed

Christensen, Pia Crone; Welch, Nicole Cheryl; Brideau, Craig; Stys, Peter K

2016-09-01

Neurotransmitter-dependent signaling is traditionally restricted to axon terminals. However, receptors are present on myelinating glia, suggesting that chemical transmission may also occur along axons. Confocal microscopy and Ca(2+) -imaging using an axonally expressed FRET-based reporter was used to measure Ca(2+) changes and morphological alterations in myelin in response to stimulation of glutamate receptors. Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors induced a Ca(2+) increase in axon cylinders. However, only the latter caused structural alterations in axons, despite similar Ca(2+) increases. Myelin morphology was significantly altered by NMDA receptor activation, but not by AMPA receptors. Cu(2+) ions influenced the NMDA receptor-dependent response, suggesting that this metal modulates axonal receptors. Glutamate increased ribosomal signal in Schwann cell cytoplasm. Axon cylinders and myelin of peripheral nervous system axons respond to glutamate, with a consequence being an increase in Schwann cell ribosomes. This may have implications for nerve pathology and regeneration. Muscle Nerve 54: 451-459, 2016. © 2016 Wiley Periodicals, Inc.

Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

PubMed Central

Ko, Hyo Rim; Kwon, Il-Sun; Hwang, Inwoo; Jin, Eun-Ju; Shin, Joo-Ho; Brennan-Minnella, Angela M; Swanson, Raymond; Cho, Sung-Woo; Lee, Kyung-Hoon; Ahn, Jee-Yin

2016-01-01

Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration. DOI: http://dx.doi.org/10.7554/eLife.20799.001 PMID:27938661

Dynamic expression of transcription factor Brn3b during mouse cranial nerve development

PubMed Central

Sajgo, Szilard; Ali, Seid; Popescu, Octavian; Badea, Tudor Constantin

2015-01-01

During development transcription factor combinatorial codes define a large variety of morphologically and physiologically distinct neurons. Such a combinatorial code has been proposed for the differentiation of projection neurons of the somatic and visceral components of cranial nerves. It is possible that individual neuronal cell types are not specified by unique transcription factors, but rather emerge through the intersection of their expression domains. Brn3a, Brn3b and Brn3c, in combination with each other and/or transcription factors of other families, can define subgroups of Retinal Ganglion Cells (RGC), Spiral and Vestibular Ganglia, inner ear and vestibular hair cell neurons in the vestibuloacoustic system, and groups of somatosensory neurons in the Dorsal Root Ganglia (DRG). In the present study we investigated the expression and potential role of the Brn3b transcription factor in cranial nerves and associated nuclei of the brainstem. We report the dynamic expression of Brn3b in the somatosensory component of cranial nerves II, V, VII and VIII and visceromotor nuclei of nerves VII, IX, X, as well as other brainstem nuclei during different stages of development into adult stage. We find that genetically identified Brn3bKO RGC axons show correct but delayed pathfinding during the early stages of embryonic development. However loss of Brn3b does not affect the anatomy of the other cranial nerves normally expressing this transcription factor. PMID:26356988

Modification of tenascin-R expression following unilateral labyrinthectomy in rats indicates its possible role in neural plasticity of the vestibular neural circuit.

PubMed

Gaal, Botond; Jóhannesson, Einar Örn; Dattani, Amit; Magyar, Agnes; Wéber, Ildikó; Matesz, Clara

2015-09-01

We have previously found that unilateral labyrinthectomy is accompanied by modification of hyaluronan and chondroitin sulfate proteoglycan staining in the lateral vestibular nucleus of rats and the time course of subsequent reorganization of extracellular matrix assembly correlates to the restoration of impaired vestibular function. The tenascin-R has repelling effect on pathfinding during axonal growth/regrowth, and thus inhibits neural circuit repair. By using immunohistochemical method, we studied the modification of tenascin-R expression in the superior, medial, lateral, and descending vestibular nuclei of the rat following unilateral labyrinthectomy. On postoperative day 1, tenascin-R reaction in the perineuronal nets disappeared on the side of labyrinthectomy in the superior, lateral, medial, and rostral part of the descending vestibular nuclei. On survival day 3, the staining intensity of tenascin-R reaction in perineuronal nets recovered on the operated side of the medial vestibular nucleus, whereas it was restored by the time of postoperative day 7 in the superior, lateral and rostral part of the descending vestibular nuclei. The staining intensity of tenascin-R reaction remained unchanged in the caudal part of the descending vestibular nucleus bilaterally. Regional differences in the modification of tenascin-R expression presented here may be associated with different roles of individual vestibular nuclei in the compensatory processes. The decreased expression of the tenascin-R may suggest the extracellular facilitation of plastic modifications in the vestibular neural circuit after lesion of the labyrinthine receptors.

Mapping the mechanical heterogeneity of the brain, and why this matters (Conference Presentation)

NASA Astrophysics Data System (ADS)

Guck, Jochen R.

2017-02-01

It is increasingly recognized that cells measure and respond to the mechanics of their environment. We are especially interested in this mechanosensing during CNS development and pathologies. Using quantitative scanning force microscopy we have shown that various neural tissues are very compliant (shear modulus < 1 kPa) and mechanically heterogeneous. We have recreated compliant polyacrylamide gel substrate with shear moduli between 0.1 and 30 kPa to match and exceed those of CNS tissue. Various primary neurons and glial cells have been cultured on these gels and their reaction studied. Both primary microglia and astrocytes responded to increasing substrate stiffness by changes in morphology and upregulation of inflammatory genes. Upon implantation of composite hydrogel stripes into rat brains, foreign body reactions were significantly enhanced around the stiff parts of the implant. It appears that the mechanical mismatch between a neural implant and native tissue might be at the root of foreign body reactions. Also oligodendrocytes are mechanosensitive as their survival, proliferation, migration, and differentiation capacity in vitro depend on substrate stiffness. This finding might be linked to the failure of remyelination in chronic demyelinating diseases such as multiple sclerosis. And finally, we have also shown retinal ganglion axon pathfinding in the early embryonic Xenopus brain development to be instructed by stiffness gradients. These results form the basis for further investigations into the mechanobiology of cell function in the CNS. Ultimately, this research could help treating previously incurable neuropathologies such as spinal cord injuries and neurodegenerative disorders.

Genetic Elimination of GABAergic Neurotransmission Reveals Two Distinct Pacemakers for Spontaneous Waves of Activity in the Developing Mouse Cortex

PubMed Central

Easton, Curtis R.; Weir, Keiko; Scott, Adina; Moen, Samantha P.; Barger, Zeke; Folch, Albert; Hevner, Robert F.

2014-01-01

Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves. PMID:24623764

Drosophila melanogaster Hedgehog cooperates with Frazzled to guide axons through a non-canonical signalling pathway.

PubMed

Ricolo, Delia; Butí, Elisenda; Araújo, Sofia J

2015-08-01

We report that the morphogen Hedgehog (Hh) is an axonal chemoattractant in the midline of Drosophila melanogaster embryos. Hh is present in the ventral nerve cord during axonal guidance and overexpression of hh in the midline causes ectopic midline crossing of FasII-positive axonal tracts. In addition, we show that Hh influences axonal guidance via a non-canonical signalling pathway dependent on Ptc. Our results reveal that the Hh pathway cooperates with the Netrin/Frazzled pathway to guide axons through the midline in invertebrates. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Calcium overloading in traumatic axonal injury by lateral head rotation: a morphological evidence in rat model.

PubMed

He, Xiao-Sheng; Xiang, Zhang; Zhou, Fei; Fu, Luo-An; Shuang, Wang

2004-05-01

The study investigated morphologically axonal calcium overloading and its relationship with axonal structural changes. Twelve SD rats were divided into an injury and a sham group. The rat model of traumatic axonal injury (TAI) by lateral head rotation was produced. The oxalate-pyroantimonate technique for calcium localization was used to process the rat's medulla oblongata tissues with thin sections observed electron-microscopically for axonal structure and calcium precipitates on it. The axonal damage in medulla oblongata appeared at 2 h post-injury, gradually became diffuse and severe, and continued to exist at 24 hours. At 2 hours, calcium precipitates were deposited on separated lamellae and axolemma, but were rarely distributed in the axoplasm. At 6 hours, calcium precipitates occurred on separated lamellae and axolemma in much higher density, but on axoplasm in extremely small amounts. Some axons, though lacking structural changes of the myelin sheath, sequestered plenty of calcium deposits on their swollen mitochondria. At 24 hours, damaged axons presented with much more severe lamellae separation and calcium deposits. Axonal calcium overloading developed in rat TAI model using lateral head rotation. This was significantly related to structural damage in the axons. These findings suggest the feasibility of using calcium antagonists in cope the management of human DAI in its very early stage.

Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation.

PubMed

Grill, Warren M; Cantrell, Meredith B; Robertson, Matthew S

2008-02-01

Electrical stimulation of the central nervous system creates both orthodromically propagating action potentials, by stimulation of local cells and passing axons, and antidromically propagating action potentials, by stimulation of presynaptic axons and terminals. Our aim was to understand how antidromic action potentials navigate through complex arborizations, such as those of thalamic and basal ganglia afferents-sites of electrical activation during deep brain stimulation. We developed computational models to study the propagation of antidromic action potentials past the bifurcation in branched axons. In both unmyelinated and myelinated branched axons, when the diameters of each axon branch remained under a specific threshold (set by the antidromic geometric ratio), antidromic propagation occurred robustly; action potentials traveled both antidromically into the primary segment as well as "re-orthodromically" into the terminal secondary segment. Propagation occurred across a broad range of stimulation frequencies, axon segment geometries, and concentrations of extracellular potassium, but was strongly dependent on the geometry of the node of Ranvier at the axonal bifurcation. Thus, antidromic activation of axon terminals can, through axon collaterals, lead to widespread activation or inhibition of targets remote from the site of stimulation. These effects should be included when interpreting the results of functional imaging or evoked potential studies on the mechanisms of action of DBS.

Learning to swim, again: Axon regeneration in fish.

PubMed

Rasmussen, Jeffrey P; Sagasti, Alvaro

2017-01-01

Damage to the central nervous system (CNS) of fish can often be repaired to restore function, but in mammals recovery from CNS injuries usually fails due to a lack of axon regeneration. The relatively growth-permissive environment of the fish CNS may reflect both the absence of axon inhibitors found in the mammalian CNS and the presence of pro-regenerative environmental factors. Despite their different capacities for axon regeneration, many of the physiological processes, intrinsic molecular pathways, and cellular behaviors that control an axon's ability to regrow are conserved between fish and mammals. Fish models have thus been useful both for identifying factors differing between mammals and fish that may account for differences in CNS regeneration and for characterizing conserved intrinsic pathways that regulate axon regeneration in all vertebrates. The majority of adult axon regeneration studies have focused on the optic nerve or spinal axons of the teleosts goldfish and zebrafish, which have been productive models for identifying genes associated with axon regeneration, cellular mechanisms of circuit reestablishment, and the basis of functional recovery. Lampreys, which are jawless fish lacking myelin, have provided an opportunity to study regeneration of well defined spinal cord circuits. Newer larval zebrafish models offer numerous genetic tools and the ability to monitor the dynamic behaviors of extrinsic cell types regulating axon regeneration in live animals. Recent advances in imaging and gene editing methods are making fish models yet more powerful for investigating the cellular and molecular underpinnings of axon regeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

Antisense Morpholino Oligonucleotides Reduce Neurofilament Synthesis and Inhibit Axon Regeneration in Lamprey Reticulospinal Neurons.

PubMed

Zhang, Guixin; Jin, Li-qing; Hu, Jianli; Rodemer, William; Selzer, Michael E

2015-01-01

The sea lamprey has been used as a model for the study of axonal regeneration after spinal cord injury. Previous studies have suggested that, unlike developing axons in mammal, the tips of regenerating axons in lamprey spinal cord are simple in shape, packed with neurofilaments (NFs), and contain very little F-actin. Thus it has been proposed that regeneration of axons in the central nervous system of mature vertebrates is not based on the canonical actin-dependent pulling mechanism of growth cones, but involves an internal protrusive force, perhaps generated by the transport or assembly of NFs in the distal axon. In order to assess this hypothesis, expression of NFs was manipulated by antisense morpholino oligonucleotides (MO). A standard, company-supplied MO was used as control. Axon retraction and regeneration were assessed at 2, 4 and 9 weeks after MOs were applied to a spinal cord transection (TX) site. Antisense MO inhibited NF180 expression compared to control MO. The effect of inhibiting NF expression on axon retraction and regeneration was studied by measuring the distance of axon tips from the TX site at 2 and 4 weeks post-TX, and counting the number of reticulospinal neurons (RNs) retrogradely labeled by fluorescently-tagged dextran injected caudal to the injury at 9 weeks post-TX. There was no statistically significant effect of MO on axon retraction at 2 weeks post-TX. However, at both 4 and 9 weeks post-TX, inhibition of NF expression inhibited axon regeneration.

Axonal ensheathment and septate junction formation in the peripheral nervous system of Drosophila.

PubMed

Banerjee, Swati; Pillai, Anilkumar M; Paik, Raehum; Li, Jingjun; Bhat, Manzoor A

2006-03-22

Axonal insulation is critical for efficient action potential propagation and normal functioning of the nervous system. In Drosophila, the underlying basis of nerve ensheathment is the axonal insulation by glial cells and the establishment of septate junctions (SJs) between glial cell membranes. However, the details of the cellular and molecular mechanisms underlying axonal insulation and SJ formation are still obscure. Here, we report the characterization of axonal insulation in the Drosophila peripheral nervous system (PNS). Targeted expression of tau-green fluorescent protein in the glial cells and ultrastructural analysis of the peripheral nerves allowed us to visualize the glial ensheathment of axons. We show that individual or a group of axons are ensheathed by inner glial processes, which in turn are ensheathed by the outer perineurial glial cells. SJs are formed between the inner and outer glial membranes. We also show that Neurexin IV, Contactin, and Neuroglian are coexpressed in the peripheral glial membranes and that these proteins exist as a complex in the Drosophila nervous system. Mutations in neurexin IV, contactin, and neuroglian result in the disruption of blood-nerve barrier function in the PNS, and ultrastructural analyses of the mutant embryonic peripheral nerves show loss of glial SJs. Interestingly, the murine homologs of Neurexin IV, Contactin, and Neuroglian are expressed at the paranodal SJs and play a key role in axon-glial interactions of myelinated axons. Together, our data suggest that the molecular machinery underlying axonal insulation and axon-glial interactions may be conserved across species.

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis elegans

PubMed Central

Xu, Yan; Ren, Xing-Cong; Quinn, Christopher C.; Wadsworth, William G.

2011-01-01

Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in culture, and it has been suggested that acetylcholine could act as a guidance cue. However, the role acetylcholine plays in directing axon migrations in vivo is not clear. Here, we show that acetylcholine positively regulates signaling pathways that mediate axon responses to guidance cues in Caenorhabditis elegans. Mutations that disrupt acetylcholine synthesis, transportation, and secretion affect circumferential axon guidance of the AVM neuron and in these mutants exogenously supplied acetylcholine improves AVM circumferential axon guidance. These effects are not observed for the circumferential guidance of the DD and VD motor neuron axons, which are neighbors of the AVM axon. Circumferential guidance is directed by the UNC-6 (netrin) and SLT-1 (slit) extracellular cues, and exogenously supplied acetylcholine can improve AVM axon guidance in mutants when either UNC-6– or SLT-1–induced signaling is disrupted, but not when both signaling pathways are perturbed. Not in any of the mutants does exogenously supplied acetylcholine improve DD and VD axon guidance. The ability of acetylcholine to enhance AVM axon guidance only in the presence of either UNC-6 or SLT-1 indicates that acetylcholine potentiates UNC-6 and SLT-1 guidance activity, rather than acting itself as a guidance cue. Together, our results show that for specific neurons acetylcholine plays an important role in vivo as a modulator of axon responses to guidance cues. PMID:21868605

A HuD-ZBP1 ribonucleoprotein complex localizes GAP-43 mRNA into axons through its 3′ untranslated region AU-rich regulatory element

PubMed Central

Yoo, Soonmoon; Kim, Hak Hee; Kim, Paul; Donnelly, Christopher J.; Kalinski, Ashley L.; Vuppalanchi, Deepika; Park, Michael; Lee, Seung Joon; Merianda, Tanuja T.; Perrone-Bizzozero, Nora I.; Twiss, Jeffery L.

2013-01-01

Localized translation of axonal mRNAs contributes to developmental and regenerative axon growth. Although untranslated regions (UTRs) of many different axonal mRNAs appear to drive their localization, there has been no consensus RNA structure responsible for this localization. We recently showed that limited expression of ZBP1 protein restricts axonal localization of both β-actin and GAP-43 mRNAs. β-actin 3′UTR has a defined element for interaction with ZBP1, but GAP-43 mRNA shows no homology to this RNA sequence. Here, we show that an AU-rich element (ARE) in GAP-43’s 3′UTR is necessary and sufficient for its axonal localization. Axonal GAP-43 mRNA levels increase after in vivo injury, and GAP-43 mRNA shows an increased half-life in regenerating axons. GAP-43 mRNA interacts with both HuD and ZBP1, and HuD and ZBP1 coimmunoprecipitate in an RNA-dependent fashion. Reporter mRNA with the GAP-43 ARE competes with endogenous β-actin mRNA for axonal localization and decreases axon length and branching similar to the β-actin 3′UTR competing with endogenous GAP-43 mRNA. Conversely, overexpressing GAP-43 coding sequence with it’s 3′UTR ARE increases axonal elongation and this effect is lost when just the ARE is deleted from GAP-43’s 3′UTR. PMID:23586486

Pharmacologically inhibiting kinesin-5 activity with monastrol promotes axonal regeneration following spinal cord injury

PubMed Central

Xu, Chen; Klaw, Michelle C.; Lemay, Michel A.; Baas, Peter W.; Tom, Veronica J.

2014-01-01

While it is well established that the axons of adult neurons have a lower capacity for regrowth, some regeneration of certain CNS populations after spinal cord injury (SCI) is possible if their axons are provided with a permissive substrate, such as an injured peripheral nerve. While some axons readily regenerate into a peripheral nerve graft (PNG), these axons almost always stall at the distal interface and fail to re-innervate spinal cord tissue. Treatment of the glial scar at the distal graft interface with chondroitinase ABC (ChABC) can improve regeneration, but most regenerated axons need further stimulation to extend beyond the interface. Previous studies demonstrate that pharmacologically inhibiting kinesin-5, a motor protein best known for its essential role in mitosis but also expressed in neurons, with the pharmacological agent monastrol increases axon growth on inhibitory substrates in vitro. We sought to determine if monastrol treatment after a SCI improves functional axon regeneration. Animals received complete thoracic level 7 (T7) transections and PNGs and were treated intrathecally with ChABC and either monastrol or DMSO vehicle. We found that combining ChABC with monastrol significantly enhanced axon regeneration. However, there were no further improvements in function or enhanced c-Fos induction upon stimulation of spinal cord rostral to the transection. This indicates that monastrol improves ChABC-mediated axon regeneration but that further treatments are needed to enhance the integration of these regrown axons. PMID:25447935

Cell intrinsic control of axon regeneration

PubMed Central

Mar, Fernando M; Bonni, Azad; Sousa, Mónica M

2014-01-01

Although neurons execute a cell intrinsic program of axonal growth during development, following the establishment of connections, the developmental growth capacity declines. Besides environmental challenges, this switch largely accounts for the failure of adult central nervous system (CNS) axons to regenerate. Here, we discuss the cell intrinsic control of axon regeneration, including not only the regulation of transcriptional and epigenetic mechanisms, but also the modulation of local protein translation, retrograde and anterograde axonal transport, and microtubule dynamics. We further explore the causes underlying the failure of CNS neurons to mount a vigorous regenerative response, and the paradigms demonstrating the activation of cell intrinsic axon growth programs. Finally, we present potential mechanisms to support axon regeneration, as these may represent future therapeutic approaches to promote recovery following CNS injury and disease. PMID:24531721

Mars Pathfinder [foldout].

PubMed

1997-12-05

The following foldout present images and analysis from the Mars Pathfinder Mission that are discussed in seven subsequent Reports. The center is a four-page panorama of the surface of Mars around the lander (Plate 1). The back of the foldout contains surface images (Plate 7), a different perspective of the landing site (Plate 2), rover targets (Plate 3), locations of rocks and other features (Plate 6) and data analysis (Plates 4, 4, 8, 9, and 10).

Mars Pathfinder Project: Planetary Constants and Models

NASA Technical Reports Server (NTRS)

Vaughan, Robin

1995-01-01

This document provides a common set of astrodynamic constants and planetary models for use by the Mars Pathfinder Project. It attempts to collect in a single reference all the quantities and models in use across the project during development and for mission operations. These models are central to the navigation and mission design functions, but they are also used in other aspects of the project such as science observation planning and data reduction.

LISA Pathfinder first results

NASA Astrophysics Data System (ADS)

Vetrugno, D.

LISA Pathfinder (LPF) is an in-flight technological demonstrator designed and launched to prove the feasibility of sub-femto-g free fall of kilo-sized test masses (TM), an essential ingredient for the future gravitational wave observatory from space. Half a year after launch, the first results are available and show an incredibly well-performing instrument. The results represent a first and important step towards the long awaited construction and launch of LISA, the Laser Interferometer Space Antenna.

Combination of Engineered Schwann Cell Grafts to Secrete Neurotrophin and Chondroitinase Promotes Axonal Regeneration and Locomotion after Spinal Cord Injury

PubMed Central

Pressman, Yelena; Moody, Alison; Berg, Randall; Muir, Elizabeth M.; Rogers, John H.; Ozawa, Hiroshi; Itoi, Eiji; Pearse, Damien D.; Bunge, Mary Bartlett

2014-01-01

Transplantation of Schwann cells (SCs) is a promising therapeutic strategy for spinal cord repair. SCs introduced into lesions support axon regeneration, but because these axons do not exit the transplant, additional approaches with SCs are needed. Here, we transplanted SCs genetically modified to secrete a bifunctional neurotrophin (D15A) and chondroitinase ABC (ChABC) into a subacute contusion injury in rats. We examined the effects of these modifications on graft volume, SC number, degradation of chondroitin sulfate proteoglycans (CSPGs), astrogliosis, SC myelination of axons, propriospinal and supraspinal axon numbers, locomotor outcome (BBB scoring, CatWalk gait analysis), and mechanical and thermal sensitivity on the hind paws. D15A secreted from transplanted SCs increased graft volume and SC number and myelinated axon number. SCs secreting ChABC significantly decreased CSPGs, led to some egress of SCs from the graft, and increased propriospinal and 5-HT-positive axons in the graft. SCs secreting both D15A and ChABC yielded the best responses: (1) the largest number of SC myelinated axons, (2) more propriospinal axons in the graft and host tissue around and caudal to it, (3) more corticospinal axons closer to the graft and around and caudal to it, (4) more brainstem neurons projecting caudal to the transplant, (5) increased 5-HT-positive axons in the graft and caudal to it, (6) significant improvement in aspects of locomotion, and (7) improvement in mechanical and thermal allodynia. This is the first evidence that the combination of SC transplants engineered to secrete neurotrophin and chondroitinase further improves axonal regeneration and locomotor and sensory function. PMID:24478364

Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat

PubMed Central

Cao, Y.; Shumsky, J. S.; Sabol, M. A.; Kushner, R. A.; Strittmatter, S.; Hamers, F. P. T.; Lee, D. H. S.; Rabacchi, S. A.; Murray, M.

2010-01-01

Objective The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). Methods Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. Results Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5 HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. Conclusions NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors’ results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons. PMID:18056009

VR for Mars Pathfinder

NASA Technical Reports Server (NTRS)

Blackmon, Theodore

1998-01-01

Virtual reality (VR) technology has played an integral role for Mars Pathfinder mission, operations Using an automated machine vision algorithm, the 3d topography of the Martian surface was rapidly recovered fro -a the stereo images captured. by the Tender camera to produce photo-realistic 3d models, An advanced, interface was developed for visualization and interaction with. the virtual environment of the Pathfinder landing site for mission scientists at the Space Flight Operations Facility of the Jet Propulsion Laboratory. The VR aspect of the display allowed mission scientists to navigate on Mars in Bud while remaining here on Earth, thus improving their spatial awareness of the rock field that surrounds the lenders Measurements of positions, distances and angles could be easily extracted from the topographic models, providing valuable information for science analysis and mission. planning. Moreover, the VR map of Mars has also been used to assist with the archiving and planning of activities for the Sojourner rover.

The Development of a Novel High Throughput Computational Tool for Studying Individual and Collective Cellular Migration

PubMed Central

Chapnick, Douglas A.; Jacobsen, Jeremy; Liu, Xuedong

2013-01-01

Understanding how cells migrate individually and collectively during development and cancer metastasis can be significantly aided by a computation tool to accurately measure not only cellular migration speed, but also migration direction and changes in migration direction in a temporal and spatial manner. We have developed such a tool for cell migration researchers, named Pathfinder, which is capable of simultaneously measuring the migration speed, migration direction, and changes in migration directions of thousands of cells both instantaneously and over long periods of time from fluorescence microscopy data. Additionally, we demonstrate how the Pathfinder software can be used to quantify collective cell migration. The novel capability of the Pathfinder software to measure the changes in migration direction of large populations of cells in a spatiotemporal manner will aid cellular migration research by providing a robust method for determining the mechanisms of cellular guidance during individual and collective cell migration. PMID:24386097

The LISA Pathfinder Mission: Sub-picometer Interferometry in Space

NASA Astrophysics Data System (ADS)

Slutsky, Jacob; LISA Pathfinder Collaboration

2018-01-01

The European Space Agency’s LISA Pathfinder was a mission built to demonstrate the technologies essential to implement a space-based gravitational wave observatory sensitive in the milli-Hertz frequency band. ESA recently selected the LISA mission as such a future observatory, scheduled to launch in the early 2030s. LISA Pathfinder launched in late 2015 and concluded its final extended mission in July 2017, during which time it placed the two test masses into free fall and successfully measured the relative acceleration between them to a sensitivity that validates a number of critical technologies for LISA. These include drag-free control of the test masses, low noise microNewton thrusters to control the spacecraft, and sub-picometer-level laser metrology in space. The mission also served as a sensitive probe of the environmenal conditions in which LISA will operate. This poster summarizes the recent analysis results, with an eye towards the implications for the LISA mission.

Rover Touchdown on Martian Surface

NASA Image and Video Library

1997-07-06

This picture taken by the IMP (Imager for Mars Pathfinder) aboard the Mars Pathfinder spacecraft depicts the rover Sojourner's position after driving onto the Martian surface. Sojourner has become the first autonomous robot ever to traverse the surface of Mars. This image reflects the success of Pathfinder's principle objective -- to place a payload on Mars in a safe, operational configuration. The primary mission of Sojourner, scheduled to last seven days, will be to use its Alpha Proton X-ray Spectrometer (APXS) instrument to determine the elements that make up the rocks and soil on Mars. A full study using the APXS takes approximately ten hours, and can measure all elements except hydrogen at any time of the Martian day or night. The APXS will conduct its studies by bombarding rocks and soil samples with alpha particle radiation -- charged particles equivalent to the nucleus of a helium atom, consisting of two protons and two neutrons. http://photojournal.jpl.nasa.gov/catalog/PIA00623

Pooh Bear rock and Mermaid Dune

NASA Technical Reports Server (NTRS)

1997-01-01

One of the two forward cameras aboard Sojourner imaged this area of Martian terrain on Sol 26. The large rock dubbed 'Pooh Bear' is at far left, and stands between four and five inches high. Mermaid Dune is the smooth area stretching horizontally across the top quarter of the image. The Alpha Proton X-Ray Spectrometer (APXS) instrument aboard Sojourner will be deployed on Mermaid Dune, and the rover will later use its cleated wheels to dig into it.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages and Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wass, P. J.; Araujo, H.; Sumner, T.

We present the concept, design and testing of the radiation monitor for LISA Pathfinder. Galactic cosmic rays (GCRs) and solar energetic particles (SEPs) will cause charging of the LISA Pathfinder test masses producing unwanted disturbances which could be significant during a large solar eruption. A radiation monitor on board LISA Pathfinder, using silicon PIN diodes as particle detectors, will measure the particle flux responsible for charging. It will also be able to record spectral information to identify solar energetic particle events. The design of the monitor was supported by Monte Carlo simulations which allow detailed predictions of the radiation monitormore » performance. We present these predictions as well as the results of high-energy proton tests carried out at the Paul Scherrer Institute, Switzerland. The tests show good agreement with our simulations and confirm the capability of the radiation monitor to perform well in the space environment, meeting all science requirements.« less

Occurrence of nonspecific reactions among stool specimens tested by the Abbott TestPack rotavirus enzyme immunoassay.

PubMed Central

Lipson, S M; Leonardi, G P; Salo, R J; Schutzbank, T E; Kaplan, M H

1990-01-01

Sixty-five stool specimens obtained from children suffering from gastroenteritis were tested for the presence of antigen to rotavirus by the Abbott TestPack Rotavirus (TestPack) enzyme immunoassay kit. The Kallestad Pathfinder enzyme immunoassay, polyacrylamide gel electrophoresis, immune electron microscopy, and virus isolation were utilized as reference assays. Fifty-four specimens were in accord by TestPack and Kallestad Pathfinder. Among 11 discordant specimens positive with TestPack but negative by Kallestad Pathfinder, rotavirus was not identified by polyacrylamide gel electrophoresis, immune electron microscopy, or isolation in primary African green monkey kidney cell cultures. TestPack displayed a performance specificity of 83%. The inordinately high number of stool specimens reported as false-positive by TestPack precludes the incorporation of this antigen detection kit into our routine regimen of diagnostic virologic testing. Images PMID:2166074

Validation of Interannual Differences of AIRS Monthly Mean Parameters

NASA Technical Reports Server (NTRS)

Susskind, Joel; Iredell, Lena; Keita, Fricky; Molnar, Gyula

2005-01-01

Monthly mean fields of select geophysical parameters derived from analysis of AIRS/AMSU data, and their interannual differences, are shown and compared with analogous fields derived from other sources. All AIRS fields are derived using the AIRS Science Team Version 4 algorithm. Monthly mean results are shown for January 2004, as are interannual differences between January 2004 and January 2003. AIRS temperature and water vapor profile fields are compared with monthly mean collocated ECMWF 3 hour forecast and monthly mean TOVS Pathfinder Path A data. AIRS Tropospheric and Stratospheric coarse climate indicators are compared with analogous MSU products derived by Spencer and christy and found in the TOVS Pathfinder Path A data set. Total ozone is compared with results produced by TOMS. OLR is compared with OLR derived using CERES data and found in the TOVS Pathfinder Path A data set. AIRS results agree well in all cases, especially in the interannual difference sense.

Herpes Simplex Virus Membrane Proteins gE/gI and US9 Act Cooperatively To Promote Transport of Capsids and Glycoproteins from Neuron Cell Bodies into Initial Axon Segments

PubMed Central

Howard, Paul W.; Howard, Tiffani L.

2013-01-01

Herpes simplex virus (HSV) and other alphaherpesviruses must move from sites of latency in ganglia to peripheral epithelial cells. How HSV navigates in neuronal axons is not well understood. Two HSV membrane proteins, gE/gI and US9, are key to understanding the processes by which viral glycoproteins, unenveloped capsids, and enveloped virions are transported toward axon tips. Whether gE/gI and US9 function to promote the loading of viral proteins onto microtubule motors in neuron cell bodies or to tether viral proteins onto microtubule motors within axons is not clear. One impediment to understanding how HSV gE/gI and US9 function in axonal transport relates to observations that gE−, gI−, or US9− mutants are not absolutely blocked in axonal transport. Mutants are significantly reduced in numbers of capsids and glycoproteins in distal axons, but there are less extensive effects in proximal axons. We constructed HSV recombinants lacking both gE and US9 that transported no detectable capsids and glycoproteins to distal axons and failed to spread from axon tips to adjacent cells. Live-cell imaging of a gE−/US9− double mutant that expressed fluorescent capsids and gB demonstrated >90% diminished capsids and gB in medial axons and no evidence for decreased rates of transport, stalling, or increased retrograde transport. Instead, capsids, gB, and enveloped virions failed to enter proximal axons. We concluded that gE/gI and US9 function in neuron cell bodies, in a cooperative fashion, to promote the loading of HSV capsids and vesicles containing glycoproteins and enveloped virions onto microtubule motors or their transport into proximal axons. PMID:23077321

Roof Plate-Derived Radial Glial-like Cells Support Developmental Growth of Rapidly Adapting Mechanoreceptor Ascending Axons.

PubMed

Kridsada, Kim; Niu, Jingwen; Haldipur, Parthiv; Wang, Zhiping; Ding, Long; Li, Jian J; Lindgren, Anne G; Herrera, Eloisa; Thomas, Gareth M; Chizhikov, Victor V; Millen, Kathleen J; Luo, Wenqin

2018-06-05

Spinal cord longitudinal axons comprise some of the longest axons in our body. However, mechanisms that drive this extra long-distance axonal growth are largely unclear. We found that ascending axons of rapidly adapting (RA) mechanoreceptors closely abut a previously undescribed population of roof plate-derived radial glial-like cells (RGLCs) in the spinal cord dorsal column, which form a network of processes enriched with growth-promoting factors. In dreher mutant mice that lack RGLCs, the lengths of ascending RA mechanoreceptor axon branches are specifically reduced, whereas their descending and collateral branches, and other dorsal column and sensory pathways, are largely unaffected. Because the number and intrinsic growth ability of RA mechanoreceptors are normal in dreher mice, our data suggest that RGLCs provide critical non-cell autonomous growth support for the ascending axons of RA mechanoreceptors. Together, our work identifies a developmental mechanism specifically required for long-range spinal cord longitudinal axons. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology

PubMed Central

Gowrishankar, Swetha; Wu, Yumei

2017-01-01

Lysosomes robustly accumulate within axonal swellings at Alzheimer’s disease (AD) amyloid plaques. However, the underlying mechanisms and disease relevance of such lysosome accumulations are not well understood. Motivated by these problems, we identified JNK-interacting protein 3 (JIP3) as an important regulator of axonal lysosome transport and maturation. JIP3 knockout mouse neuron primary cultures accumulate lysosomes within focal axonal swellings that resemble the dystrophic axons at amyloid plaques. These swellings contain high levels of amyloid precursor protein processing enzymes (BACE1 and presenilin 2) and are accompanied by elevated Aβ peptide levels. The in vivo importance of the JIP3-dependent regulation of axonal lysosomes was revealed by the worsening of the amyloid plaque pathology arising from JIP3 haploinsufficiency in a mouse model of AD. These results establish the critical role of JIP3-dependent axonal lysosome transport in regulating amyloidogenic amyloid precursor protein processing and support a model wherein Aβ production is amplified by plaque-induced axonal lysosome transport defects. PMID:28784610

Axonal Transport: How High Microtubule Density Can Compensate for Boundary Effects in Small-Caliber Axons

PubMed Central

Wortman, Juliana C.; Shrestha, Uttam M.; Barry, Devin M.; Garcia, Michael L.; Gross, Steven P.; Yu, Clare C.

2014-01-01

Long-distance intracellular axonal transport is predominantly microtubule-based, and its impairment is linked to neurodegeneration. In this study, we present theoretical arguments that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Our theoretical analysis suggests that this opposition to motion increases rapidly as the cargo approaches the wall. We find that having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus minimizes the effects of any opposition to transport. Even if microtubules are randomly placed in axons, we find that the higher density of microtubules found in small-caliber axons increases the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. The boundary effect is not a factor in transport in large-caliber axons where the microtubule density is lower. PMID:24559984

Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration

PubMed Central

Cosker, Katharina E.; Pazyra-Murphy, Maria F.; Fenstermacher, Sara J.

2013-01-01

Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target-derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation can be integrated over time, so that axonal survival is restricted to neurons connected within a stable circuit. PMID:23516285

GDF10 Is a Signal for Axonal Sprouting and Functional Recovery after Stroke

PubMed Central

Li, S; Nie, EH; Yin, Y; Benowitz, LI; Tung, S; Vinters, HV; Bahjat, FR; Stenzel-Poore, MP; Kawaguchi, R; Coppola, G; Carmichael, ST

2016-01-01

Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and Differentiation Factor 10 (GDF10) is induced in peri-infarct neurons in mouse, non-human primate and human. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFβRI/II signaling. Using pharmacogenetic gain and loss of function studies, GDF10 produces axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocks axonal sprouting and reduces recovery. RNA-seq from peri-infarct cortical neurons indicates that GDF10 downregulates PTEN and upregulates PI3 kinase signaling and induces specific axonal guidance molecules. Unsupervised genome-wide association analysis of the GDF10 transcriptome shows that it is not related to neurodevelopment but may partially overlap with other CNS injury patterns. GDF10 is a stroke-induced signal for axonal sprouting and functional recovery. PMID:26502261

Axonal Transport and Morphology: How Myelination gets Nerves into Shape

NASA Astrophysics Data System (ADS)

Jung, Peter; Zhao, Peng; Monsma, Paula; Brown, Tony

2011-03-01

The local caliber of mature axons is largely determined by neurofilament (NF) content. The axoskeleton, mainly consisting of NFs, however, is dynamic. NFs are assembled in the cell body and are transported by molecular motors on microtubule tracks along the axon at a slow rate of fractions of mm per day. We combine live cell fluorescent imaging techniques to access NF transport in myelinated and non-myelinated segments of axons with computational modeling of the active NF flow to show that a), myelination locally slows NF transport rates by regulating duty ratios and b), that the predicted increase in axon caliber agrees well with experiments. This study, for the first time, links NF kinetics directly to axonal morphology, providing a novel conceptual framework for the physical understanding of processes leading to the formation of axonal structures such as the ``Nodes of Ranvier'' as well as abnormal axonal swellings associated with neurodegenerative diseases like Amyotrophic lateral sclerosis (ALS). NSF grants # IOS-0818412(PJ) and IOS-0818653 (AB).

Reversing the Outcome of Synapse Elimination at Developing Neuromuscular Junctions In Vivo: Evidence for Synaptic Competition and Its Mechanism

PubMed Central

Turney, Stephen G.; Lichtman, Jeff W.

2012-01-01

During mammalian development, neuromuscular junctions and some other postsynaptic cells transition from multiple- to single-innervation as synaptic sites are exchanged between different axons. It is unclear whether one axon invades synaptic sites to drive off other inputs or alternatively axons expand their territory in response to sites vacated by other axons. Here we show that soon-to-be-eliminated axons rapidly reverse fate and grow to occupy vacant sites at a neuromuscular junction after laser removal of a stronger input. This reversal supports the idea that axons take over sites that were previously vacated. Indeed, during normal development we observed withdrawal followed by takeover. The stimulus for axon growth is not postsynaptic cell inactivity because axons grow into unoccupied sites even when target cells are functionally innervated. These results demonstrate competition at the synaptic level and enable us to provide a conceptual framework for understanding this form of synaptic plasticity. PMID:22745601

Axonal GABAA receptors.

PubMed

Trigo, Federico F; Marty, Alain; Stell, Brandon M

2008-09-01

Type A GABA receptors (GABA(A)Rs) are well established as the main inhibitory receptors in the mature mammalian forebrain. In recent years, evidence has accumulated showing that GABA(A)Rs are prevalent not only in the somatodendritic compartment of CNS neurons, but also in their axonal compartment. Evidence for axonal GABA(A)Rs includes new immunohistochemical and immunogold data: direct recording from single axonal terminals; and effects of local applications of GABA(A)R modulators on action potential generation, on axonal calcium signalling, and on neurotransmitter release. Strikingly, whereas presynaptic GABA(A)Rs have long been considered inhibitory, the new studies in the mammalian brain mostly indicate an excitatory action. Depending on the neuron that is under study, axonal GABA(A)Rs can be activated by ambient GABA, by GABA spillover, or by an autocrine action, to increase either action potential firing and/or transmitter release. In certain neurons, the excitatory effects of axonal GABA(A)Rs persist into adulthood. Altogether, axonal GABA(A)Rs appear as potent neuronal modulators of the mammalian CNS.

Age may contribute to the increased frequency of axonal Guillain-Barré syndrome.

PubMed

Hawkes, Maximiliano A; Wilken, Miguel; Vázquez, Gabriel; Farez, Mauricio F

2017-12-01

The frequency of axonal Guillain-Barré syndrome (GBS) varies among countries. Previous studies supporting the high frequency of axonal GBS in South America have been carried out with pediatric populations. We seek to determine the frequency of axonal GBS in both children and adults in South America. This is a retrospective cohort analysis of patients who were diagnosed with GBS between January 2006 and December 2013 in a neurological center in Buenos Aires, Argentina. Adults and children with a diagnosis of GBS were included and classified by applying Ho and colleagues' criteria 1 for axonal GBS. The study included 105 patients with GBS. Among 58 adults, only 5 individuals were classified as axonal GBS compared with 16 of 47 children. The frequency of axonal GBS was significantly higher in children than in adults (34% vs. 8.6%, P = 0.0001). As shown in a cohort of South American patients, age may impact the frequency of axonal GBS. Muscle Nerve 56: 1311-1313, 2017. © 2017 Wiley Periodicals, Inc.

Genetic analysis of an overlapping functional requirement for L1- and NCAM-type proteins during sensory axon guidance in Drosophila.

PubMed

Kristiansen, Lars V; Velasquez, Emma; Romani, Susana; Baars, Sigrid; Berezin, Vladimir; Bock, Elisabeth; Hortsch, Michael; Garcia-Alonso, Luis

2005-01-01

L1- and NCAM-type cell adhesion molecules represent distinct protein families that function as specific receptors for different axon guidance cues. However, both L1 and NCAM proteins promote axonal growth by inducing neuronal tyrosine kinase activity and are coexpressed in subsets of axon tracts in arthropods and vertebrates. We have studied the functional requirements for the Drosophila L1- and NCAM-type proteins, Neuroglian (Nrg) and Fasciclin II (FasII), during postembryonic sensory axon guidance. The rescue of the Neuroglian loss-of-function (LOF) phenotype by transgenically expressed L1- and NCAM-type proteins demonstrates a functional interchangeability between these proteins in Drosophila photoreceptor pioneer axons, where both proteins are normally coexpressed. In contrast, the ectopic expression of Fasciclin II in mechanosensory neurons causes a strong enhancement of the axonal misguidance phenotype. Moreover, our findings demonstrate that this functionally redundant specificity to mediate axon guidance has been conserved in their vertebrate homologs, L1-CAM and NCAM.

Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx

PubMed Central

Yamagishi, Yuya; Tessier-Lavigne, Marc

2015-01-01

Calcium is a key regulator of axon degeneration caused by trauma and disease, but its specific spatial and temporal dynamics in injured axons remain unclear. To clarify the function of calcium in axon degeneration, we observed calcium dynamics in single injured neurons in live zebrafish larvae and tested the temporal requirement for calcium in zebrafish neurons and cultured mouse DRG neurons. Using laser axotomy to induce Wallerian degeneration (WD) in zebrafish peripheral sensory axons, we monitored calcium dynamics from injury to fragmentation, revealing two stereotyped phases of axonal calcium influx. First, axotomy triggered a transient local calcium wave originating at the injury site. This initial calcium wave only disrupted mitochondria near the injury site and was not altered by expression of the protective WD slow (WldS) protein. Inducing multiple waves with additional axotomies did not change the kinetics of degeneration. In contrast, a second phase of calcium influx occurring minutes before fragmentation spread as a wave throughout the axon, entered mitochondria, and was abolished by WldS expression. In live zebrafish, chelating calcium after the first wave, but before the second wave, delayed the progress of fragmentation. In cultured DRG neurons, chelating calcium early in the process of WD did not alter degeneration, but chelating calcium late in WD delayed fragmentation. We propose that a terminal calcium wave is a key instructive component of the axon degeneration program. SIGNIFICANCE STATEMENT Axon degeneration resulting from trauma or neurodegenerative disease can cause devastating deficits in neural function. Understanding the molecular and cellular events that execute axon degeneration is essential for developing treatments to address these conditions. Calcium is known to contribute to axon degeneration, but its temporal requirements in this process have been unclear. Live calcium imaging in severed zebrafish neurons and temporally controlled pharmacological treatments in both zebrafish and cultured mouse sensory neurons revealed that axonal calcium influx late in the degeneration process regulates axon fragmentation. These findings suggest that temporal considerations will be crucial for developing treatments for diseases associated with axon degeneration. PMID:26558774

β1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function

PubMed Central

Kruger, Larisa C.; O'Malley, Heather A.; Hull, Jacob M.; Kleeman, Amanda; Patino, Gustavo A.

2016-01-01

Voltage-gated sodium channel (VGSC) β subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, β subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell–cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC β1 and β1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of β1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b+/W) with mice heterozygous for the Scn1b-null allele (Scn1b+/−) to determine whether the C121W mutation results in loss-of-function in vivo. We found that Scn1b+/W mice were more susceptible than Scn1b+/− and Scn1b+/+ mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. β1-C121W subunits are expressed at the neuronal cell surface in vivo. However, despite this, β1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC α subunits in the brain. β1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1bW/W mice. These data, together with our previous results showing that β1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients. SIGNIFICANCE STATEMENT The mechanisms underlying genetic epilepsy syndromes are poorly understood. Closing this gap in knowledge is essential to the development of new medicines to treat epilepsy. We have used mouse models to understand the mechanism of a mutation in the sodium channel gene SCN1B linked to genetic epilepsy with febrile seizures plus. We report that sodium channel β1 subunit proteins encoded by this mutant gene are expressed at the surface of neuronal cell bodies; however, they do not associate with the ion channel complex nor are they transported to areas of the axon that are critical for proper neuronal firing. We conclude that this disease-causing mutation is not simply a loss-of-function, but instead results in a deleterious gain-of-function in the brain. PMID:27277800

Electron microscopic examination of the myelinated axons of corpus callosum in perfused young and old rats.

PubMed

Sargon, Mustafa F; Denk, C Cem; Celik, H Hamdi; Surucu, H Selcuk; Aldur, M Mustafa

2007-07-01

In this study, the myelinated axons of parts of the corpus callosums of young and old rats were examined under the electron microscope and a grading system was performed for quantitating the ultrastructural pathological changes of these axons. Except the old splenium group, the only ultrastructural pathological change, observed in the myelinated axons was the separation in myelin configuration. In addition to this finding, in the old splenium group, in some of the myelinated axons, an interruption was observed in the myelin configuration. Additionally, these ultrastructural pathological findings were present in the larger sized myelinated axons of the corpus callosum.

A supercritical density of fast Na+ channels ensures rapid propagation of action potentials in GABAergic interneuron axons

PubMed Central

Hu, Hua; Jonas, Peter

2014-01-01

Fast-spiking, parvalbumin-expressing GABAergic interneurons/basket cells (BCs) play a key role in feedforward and feedback inhibition, gamma oscillations, and complex information processing. For these functions, fast propagation of action potentials (APs) from the soma to the presynaptic terminals is important. However, the functional properties of interneuron axons remain elusive. Here, we examined interneuron axons by confocally targeted subcellular patch-clamp recording in rat hippocampal slices. APs were initiated in the proximal axon ~20 μm from the soma, and propagated to the distal axon with high reliability and speed. Subcellular mapping revealed a stepwise increase of Na+ conductance density from the soma to the proximal axon, followed by a further gradual increase in the distal axon. Active cable modeling and experiments with partial channel block indicated that low axonal Na+ conductance density was sufficient for reliability, but high Na+ density was necessary for both speed of propagation and fast-spiking AP phenotype. Our results suggest that a supercritical density of Na+ channels compensates for the morphological properties of interneuron axons (small segmental diameter, extensive branching, and high bouton density), ensuring fast AP propagation and high-frequency repetitive firing. PMID:24657965

SRF phosphorylation by glycogen synthase kinase-3 promotes axon growth in hippocampal neurons.

PubMed

Li, Cong L; Sathyamurthy, Aruna; Oldenborg, Anna; Tank, Dharmesh; Ramanan, Narendrakumar

2014-03-12

The growth of axons is an intricately regulated process involving intracellular signaling cascades and gene transcription. We had previously shown that the stimulus-dependent transcription factor, serum response factor (SRF), plays a critical role in regulating axon growth in the mammalian brain. However, the molecular mechanisms underlying SRF-dependent axon growth remains unknown. Here we report that SRF is phosphorylated and activated by GSK-3 to promote axon outgrowth in mouse hippocampal neurons. GSK-3 binds to and directly phosphorylates SRF on a highly conserved serine residue. This serine phosphorylation is necessary for SRF activity and for its interaction with MKL-family cofactors, MKL1 and MKL2, but not with TCF-family cofactor, ELK-1. Axonal growth deficits caused by GSK-3 inhibition could be rescued by expression of a constitutively active SRF. The SRF target gene and actin-binding protein, vinculin, is sufficient to overcome the axonal growth deficits of SRF-deficient and GSK-3-inhibited neurons. Furthermore, short hairpin RNA-mediated knockdown of vinculin also attenuated axonal growth. Thus, our findings reveal a novel phosphorylation and activation of SRF by GSK-3 that is critical for SRF-dependent axon growth in mammalian central neurons.

Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration

PubMed Central

Rao, Kavitha; Stone, Michelle C.; Weiner, Alexis T.; Gheres, Kyle W.; Zhou, Chaoming; Deitcher, David L.; Levitan, Edwin S.; Rolls, Melissa M.

2016-01-01

Mutations in >50 genes, including spastin and atlastin, lead to hereditary spastic paraplegia (HSP). We previously demonstrated that reduction of spastin leads to a deficit in axon regeneration in a Drosophila model. Axon regeneration was similarly impaired in neurons when HSP proteins atlastin, seipin, and spichthyin were reduced. Impaired regeneration was dependent on genetic background and was observed when partial reduction of HSP proteins was combined with expression of dominant-negative microtubule regulators, suggesting that HSP proteins work with microtubules to promote regeneration. Microtubule rearrangements triggered by axon injury were, however, normal in all genotypes. We examined other markers to identify additional changes associated with regeneration. Whereas mitochondria, endosomes, and ribosomes did not exhibit dramatic repatterning during regeneration, the endoplasmic reticulum (ER) was frequently concentrated near the tip of the growing axon. In atlastin RNAi and spastin mutant animals, ER accumulation near single growing axon tips was impaired. ER tip concentration was observed only during axon regeneration and not during dendrite regeneration. In addition, dendrite regeneration was unaffected by reduction of spastin or atlastin. We propose that the HSP proteins spastin and atlastin promote axon regeneration by coordinating concentration of the ER and microtubules at the growing axon tip. PMID:27605706

In vivo imaging and quantitative analysis of changes in axon length using transgenic zebrafish embryos.

PubMed

Kanungo, Jyotshnabala; Lantz, Susan; Paule, Merle G

2011-01-01

We describe an imaging procedure to measure axon length in zebrafish embryos in vivo. Automated fluorescent image acquisition was performed with the ImageXpress Micro high content screening reader and further analysis of axon lengths was performed on archived images using AcuityXpress software. We utilized the Neurite Outgrowth Application module with a customized protocol (journal) to measure the axons. Since higher doses of ethanol (2-2.5%, v/v) have been shown to deform motor neurons and axons during development, here we used ethanol to treat transgenic [hb9:GFP (green fluorescent protein)] zebrafish embryos at 28 hpf (hours post-fertilization). These embryos express GFP in the motor neurons and their axons. Embryos after ethanol treatment were arrayed in 384-well plates for automated fluorescent image acquisition in vivo. Average axon lengths of high dose ethanol-treated embryos were significantly lower than the control. Another experiment showed that there was no significant difference in the axon lengths between the embryos grown for 24h at 22°C and 28.5°C. These test experiments demonstrate that using axon development as an end-point, compound screening can be performed in a time-efficient manner. Published by Elsevier Inc.

The Extract of Roots of Sophora flavescens Enhances the Recovery of Motor Function by Axonal Growth in Mice with a Spinal Cord Injury.

PubMed

Tanabe, Norio; Kuboyama, Tomoharu; Kazuma, Kohei; Konno, Katsuhiro; Tohda, Chihiro

2015-01-01

Although axonal extension to reconstruct spinal tracts should be effective for restoring function after spinal cord injury (SCI), chondroitin sulfate proteoglycan (CSPG) levels increase at spinal cord lesion sites, and inhibit axonal regrowth. In this study, we found that the water extract of roots of Sophora flavescens extended the axons of mouse cortical neurons, even on a CSPG-coated surface. Consecutive oral administrations of S. flavescens extract to SCI mice for 31 days increased the density of 5-HT-positive axons at the lesion site and improved the motor function. Further, the active constituents in the S. flavescens extract were identified. The water and alkaloid fractions of the S. flavescens extract each exhibited axonal extension activity in vitro. LC/MS analysis revealed that these fractions mainly contain matrine and/or oxymatrine, which are well-known major compounds in S. flavescens. Matrine and oxymatrine promoted axonal extension on the CSPG-coated surface. This study is the first to demonstrate that S. flavescens extract, matrine, and oxymatrine enhance axonal growth in vitro, even on a CSPG-coated surface, and that S. flavescens extract improves motor function and increases axonal density in SCI mice.

3D axon growth by exogenous electrical stimulus and soluble factors.

PubMed

Tang-Schomer, Min D

2018-01-01

Axon growth and alignment are fundamental processes during nervous system development and neural regeneration after injury. The present study investigates the effects of exogenous stimulus of electrical signals and soluble factors on axon 3D growth, using a silk protein material-based 3D brain tissue model. Electrical stimulus was delivered via embedded gold wires positioned at the interface of the scaffold region and the center matrix gel-filled region, spanning the axon growth area. This setup delivered applied electrical field directly to growing axons, and the effects were compared to micro-needle assisted local delivery of soluble factors of extracellular (ECM) components and neurotrophins. Dissociated rat cortical neurons were exposed to an alternating field of 80 mV/mm at 0.5 Hz to 2 kHz or soluble factors for up to 4 days, and evaluated by of β III-tubulin immunostaining, confocal imaging and 3D neurite tracing. 0.5-20 Hz were found to promote axon growth, with 2 Hz producing the biggest effect of ∼30% axon length increase compared to control cultures. Delivery of ECM components of laminin and fibronectin resulted significantly greater axon initial length increases compared to neurotrophic factors, such as BDNF, GDNF, NGF and NT3 (all at 1 μM). Though axon lengths under 2 Hz stimulation and LN or FN exposure were statistically similar, significant AC-induced axon alignment was found under all frequencies tested. The effects included perpendicular orientation of axons trespassing an electrode, large populations of aligned axon tracts in parallel to the field direction with a few perpendicularly aligned along the middle point of the EF. These findings are consistent with the hypothesis that an electrode in AC field could act as an alternating cathode that attracts the growing tip of the axon. These results demonstrate the use of alternating electric field stimulation to direct axon 3D length growth and orientation. Our study provides basis for further optimizing stimulation parameters, in conjunction of delivery of growth promoting soluble factors to direct axon growth in a brain mimetic 3D environment. This system provides a platform for studying the effects of exogenous signals on nervous system development and for testing neuromodulation approaches for neurological diseases. Copyright © 2017 Elsevier B.V. All rights reserved.