The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Marc Tessierlavigne - One of the best experts on this subject based on the ideXlab platform.
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regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin
Neuron, 2013Co-Authors: Dara Y Kallop, Olav Olsen, Zhuhao Wu, Robby M Weimer, Kunihiro Uryu, Nicolas Renier, Jing Yang, Marc TessierlavigneAbstract:Summary Axon degeneration is widespread both in neurodegenerative disease and in normal neural development, but the molecular pathways regulating these degenerative processes and the extent to which they are distinct or overlapping remain incompletely understood. We report that calpastatin, an inhibitor of calcium-activated proteases of the calpain family, functions as a key endogenous regulator of axon degeneration. Calpastatin depletion was observed in degenerating Axons after physical injury, and maintaining calpastatin inhibited degeneration of transected Axons in vitro and in the optic nerve in vivo. Calpastatin depletion also occurred in a caspase-dependent manner in trophic factor-deprived sensory Axons and was required for this in vitro model of developmental degeneration. In vivo, calpastatin regulated the normal pruning of retinal ganglion cell Axons in their target field. These findings identify calpastatin as a key checkpoint for axonal survival after injury and during development, and demonstrate downstream convergence of these distinct pathways of axon degeneration.
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boc is a receptor for sonic hedgehog in the guidance of commissural Axons
Nature, 2006Co-Authors: Ami Okada, Marc Tessierlavigne, Frederic Charron, Steves Morin, David S Shin, Karen Wong, Pierre J Fabre, Susan K McconnellAbstract:In the spinal cord, sonic hedgehog (Shh) is secreted by the floor plate to control the generation of distinct classes of ventral neurons along the dorsoventral axis1. Genetic and in vitro studies have shown that Shh also later acts as a midline-derived chemoattractant for commissural Axons2. However, the receptor(s) responsible for Shh attraction remain unknown. Here we show that two Robo-related proteins, Boc and Cdon, bind specifically to Shh and are therefore candidate receptors for the action of Shh as an axon guidance ligand. Boc is expressed by commissural neurons, and targeted disruption of Boc in mouse results in the misguidance of commissural Axons towards the floor plate. RNA-interference-mediated knockdown of Boc impairs the ability of rat commissural Axons to turn towards an ectopic source of Shh in vitro. Taken together, these data suggest that Boc is essential as a receptor for Shh in commissural axon guidance.
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slit1 and slit2 cooperate to prevent premature midline crossing of retinal Axons in the mouse visual system
Neuron, 2002Co-Authors: Katja Brose, Corey S Goodman, Lynda Erskine, Andrew S Plump, Christelle Sabatier, Charles J Epstein, Carol A Mason, Marc TessierlavigneAbstract:Abstract During development, retinal ganglion cell (RGC) Axons either cross or avoid the midline at the optic chiasm. In Drosophila , the Slit protein regulates midline axon crossing through repulsion. To determine the role of Slit proteins in RGC axon guidance, we disrupted Slit1 and Slit2 , two of three known mouse Slit genes. Mice defective in either gene alone exhibited few RGC axon guidance defects, but in double mutant mice a large additional chiasm developed anterior to the true chiasm, many retinal Axons projected into the contralateral optic nerve, and some extended ectopically—dorsal and lateral to the chiasm. Our results indicate that Slit proteins repel retinal Axons in vivo and cooperate to establish a corridor through which the Axons are channeled, thereby helping define the site in the ventral diencephalon where the optic chiasm forms.
Paul C. Letourneau - One of the best experts on this subject based on the ideXlab platform.
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Protein synthesis in distal Axons is not required for axon growth in the embryonic spinal cord.
Developmental neurobiology, 2007Co-Authors: Murray Blackmore, Paul C. LetourneauAbstract:It is now well established that new proteins are synthesized in the distal segments of elongating Axons, where they may play an essential role in some guidance decisions. It remains unclear, however, whether distal protein synthesis also plays an essential role in axon growth per se. Previous in vitro experiments have shown that blocking protein synthesis in distal Axons has no effect on the rate of axonal advance. However, because these experiments were performed in vitro and over a relatively short time period, the role of distal protein synthesis over longer periods and in a native tissue environment remained untested. Here, we tested whether protein synthesis in distal Axons plays an essential role in the elongation of descending Axons in the embryonic spinal cord. We developed an in situ model of the brainstem-spinal projection of the embryonic chick, and developed a split-chamber method in which inhibitors of proteins synthesis could be applied independently to cell bodies in the brainstem or to distal Axons in the spinal cord. When protein synthesis was blocked in distal Axons, axon growth remained robust for 2 days, which is the length of the experiment. However, when protein synthesis was blocked only in the brainstem, axonal elongation in the spinal cord ceased within 6 h. These data showed that protein synthesis in the distal axon is not essential to continue the advance of Axons. Rather, essential proteins are synthesized more proximally and then transported rapidly to the distal axon. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Michael E. Selzer - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Axon Elongation Following CNS Injury: What Is Happening at the Axon Tip?
Frontiers in Cellular Neuroscience, 2020Co-Authors: William Rodemer, Gianluca Gallo, Michael E. SelzerAbstract:After an injury to the central nervous system (CNS), functional recovery is limited by the inability of severed Axons to regenerate and form functional connections with appropriate target neurons beyond the injury. Despite tremendous advances in our understanding of the mechanisms of axon growth, and of the inhibitory factors in the injured CNS that prevent it, disappointingly little progress has been made in restoring function to human patients with CNS injuries, such as spinal cord injury (SCI), through regenerative therapies. Clearly, the large number of overlapping neuron-intrinsic and -extrinsic growth-inhibitory factors attenuates the benefit of neutralizing any one target. More daunting is the distances human Axons would have to regenerate to reach some threshold number of target neurons, e.g., those that occupy one complete spinal segment, compared to the distances required in most experimental models, such as mice and rats. However, the difficulties inherent in studying mechanisms of axon regeneration in the mature CNS in vivo have caused researchers to rely heavily on extrapolation from studies of axon regeneration in peripheral nerve, or of growth cone-mediated axon development in vitro and in vivo. Unfortunately, evidence from several animal models, including the transected lamprey spinal cord, has suggested important differences between regeneration of mature CNS Axons and growth of Axons in peripheral nerve, or during embryonic development. Specifically, long-distance regeneration of severed Axons may not involve the actin-myosin molecular motors that guide embryonic growth cones in developing Axons. Rather, non-growth cone-mediated axon elongation may be required to propel injured Axons in the mature CNS. If so, it may be necessary to use other experimental models to promote regeneration that is sufficient to contact a critical number of target neurons distal to a CNS lesion. This review examines the cytoskeletal underpinnings of axon growth, focusing on the elongating axon tip, to gain insights into how CNS Axons respond to injury, and how this might affect the development of regenerative therapies for SCI and other CNS injuries.
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Neurofilament spacing, phosphorylation, and axon diameter in regenerating and uninjured lamprey Axons.
The Journal of comparative neurology, 1996Co-Authors: Donald S. Pijak, Garth F. Hall, Peter J. Tenicki, Alan S. Boulos, Diana I. Lurie, Michael E. SelzerAbstract:It has been postulated that phosphorylation of the carboxy terminus sidearms of neurofilaments (NFs) increases axon diameter through repulsive electrostatic forces that increase sidearm extension and interfilament spacing. To evaluate this hypothesis, the relationships among NF phosphorylation, NF spacing, and axon diameter were examined in uninjured and spinal cord-transected larval sea lampreys (Petromyzon marinus). In untransected animals, axon diameters in the spinal cord varied from 0.5 to 50 μm. Antibodies specific for highly phosphorylated NFs labeled only large Axons (>10 μm), whereas antibodies for lightly phosphorylated NFs labeled medium-sized and small Axons more darkly than large Axons. For most Axons in untransected animals, diameter was inversely related to NF packing density, but the interfilament distances of the largest Axons were only 1.5 times those of the smallest Axons. In addition, the lightly phosphorylated NFs of the small Axons in the dorsal columns were widely spaced, suggesting that phosphorylation of NFs does not rigidly determine their spacing and that NF spacing does not rigidly determine axon diameter. Regenerating neurites of giant reticulospinal Axons (GRAs) have diameters only 5–10% of those of their parent Axons. If axon caliber is controlled by NF phosphorylation via mutual electrostatic repulsion, then NFs in the slender regenerating neurites should be lightly phosphorylated and densely packed (similar to NFs in uninjured small caliber Axons), whereas NFs in the parent GRAs should be highly phosphorylated and loosely packed. However, although linear density of NFs (the number of NFs per micrometer) in these slender regenerating neurites was twice that in their parent Axons, they were highly phosphorylated. Following sectioning of these same Axons close to the cell body, axon-like neurites regenerated ectopically from dendritic tips. These ectopically regenerating neurites had NF linear densities 2.5 times those of uncut GRAs but were also highly phosphorylated. Thus, in the lamprey, NF phosphorylation may not control axon diameter directly through electrorepulsive charges that increase NF sidearm extension and NF spacing. It is possible that phosphorylation of NFs normally influences axon diameter through indirect mechanisms, such as the slowing of NF transport and the formation of a stationary cytoskeletal lattice, as has been proposed by others. Such a mechanism could be overridden during regeneration, when a more compact, phosphorylated NF backbone might add mechanical stiffness that promotes the advance of the neurite tip within a restricted central nervous system environment. © 1996 Wiley-Liss, Inc.
Haruyuki Kamiya - One of the best experts on this subject based on the ideXlab platform.
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Excitability tuning of Axons in the central nervous system
The Journal of Physiological Sciences, 2016Co-Authors: Shunsuke Ohura, Haruyuki KamiyaAbstract:The axon is a long neuronal process that originates from the soma and extends towards the presynaptic terminals. The pioneering studies on the squid giant axon or the spinal cord motoneuron established that the axon conducts action potentials faithfully to the presynaptic terminals with self-regenerative processes of membrane excitation. Recent studies challenged the notion that the fundamental understandings obtained from the study of squid giant Axons are readily applicable to the Axons in the mammalian central nervous system (CNS). These studies revealed that the functional and structural properties of the CNS Axons are much more variable than previously thought. In this review article, we summarize the recent understandings of axon physiology in the mammalian CNS due to progress in the subcellular recording techniques which allow direct recordings from the axonal membranes, with emphasis on the hippocampal mossy fibers as a representative en passant Axons typical for cortical Axons.
John G. Flanagan - One of the best experts on this subject based on the ideXlab platform.
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MicroRNA-132 Is Enriched in Developing Axons, Locally Regulates Rasa1 mRNA, and Promotes Axon Extension
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Melissa L. Hancock, Nicolas Preitner, Jie Quan, John G. FlanaganAbstract:Developing Axons can locally synthesize proteins, with roles in axon growth, guidance, and regeneration, but the mechanisms that regulate axonal mRNA translation are not well understood. MicroRNAs (miRNAs) are important regulators of translation but have still been little characterized in developing Axons. Here we study mouse dorsal root ganglion (DRG) Axons and show that their extension is impaired by conditional deficiency of the miRNA-processing enzyme Dicer in vitro and in vivo. A screen for axonal localization identifies a specific set of miRNAs preferentially enriched within the developing axon. High axonal expression and preferential localization were observed for miR-132, a miRNA previously known for roles in dendrites and dysregulation in major neurologic diseases. miR-132 knockdown reduced extension of cultured DRG Axons, whereas overexpression increased extension. Mechanistically, miR-132 regulated the mRNA for the Ras GTPase activator Rasa1, a novel target in neuronal function. Moreover, miR-132 regulation of Rasa1 translation was seen in severed Axons, demonstrating miRNA function locally within the axon. miR-132 expression in DRGs peaked in the period of maximum axon growth in vivo, consistent with its effect on axon growth, and suggesting a role as a developmental timer. Together, these findings identify miR-132 as a positive regulator of developing axon extension, acting through repression of Rasa1 mRNA, in a mechanism that operates locally within the axon.
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axonal protein synthesis provides a mechanism for localized regulation at an intermediate target
Cell, 2002Co-Authors: Perry A Brittis, John G. FlanaganAbstract:As Axons grow past intermediate targets, they change their responsiveness to guidance cues. Local upregulation of receptor expression is involved, but the mechanisms for this are not clear. Here protein synthesis is traced within individual Axons by introducing RNAs encoding visualizable reporters. Individual severed Axons and growth cones can translate proteins and also export them to the cell surface. As Axons reach the spinal cord midline, EphA2 is among the receptors upregulated on at least some distal axon segments. Midline reporter upregulation is recapitulated by part of the EphA2 mRNA 3' untranslated region, which is highly conserved and includes known translational control sequences. These results show Axons contain all the machinery for protein translation and cell surface expression, and they reveal a potentially general and flexible RNA-based mechanism for regulation localized within a subregion of the axon.
