The Experts below are selected from a list of 3123 Experts worldwide ranked by ideXlab platform
Timothy E Kennedy - One of the best experts on this subject based on the ideXlab platform.
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Cellular/Molecular Deleted in Colorectal Cancer Binding Netrin-1 Mediates Cell Substrate Adhesion and Recruits Cdc42, Rac1, Pak1, and N-WASP into an Intracellular Signaling Complex That Promotes Growth Cone Expansion
2016Co-Authors: Masoud Shekarabi, Simonw Moore, Nicolas X. Tritsch, Stephen J. Morris, Jean-francois Bouchard, Timothy E KennedyAbstract:Extracellular cues direct Axon Extension by regulating growth conemorphology. The netrin-1 receptor deleted in colorectal cancer (DCC) is required for commissural Axon Extension to the floor plate in the embryonic spinal cord. Here we demonstrate that challenging embryonic rat spinal commissural neuronswith netrin-1, either in solution or as a substrate, causes DCC-dependent increases in growth cone surface area and filopodia number, which we term growth cone expansion. We provide evidence that DCC influences growth cone morphology by at least two mechanisms. First, DCC mediates an adhesive interaction with substrate-bound netrin-1. Second, netrin-1 binding to DCC recruits an intracellular signaling complex that directs the organization of actin. We show that netrin-1-induced growth cone expansion requires Cdc42 (cell division cycle 42), Rac1 (Ras-related C3 botulinum toxin substrate 1), Pak1 (p21-activated kinase), andN-WASP (neuronalWiskott–Aldrich syndromeprotein) and that the application of netrin-1 rapidly activates Cdc42, Rac1, andPak1. Furthermore, netrin-1 recruits Cdc42, Rac1, Pak1, and N-WASP into a complex with the intracellular domain of DCC and Nck1. These findings suggest thatDCC influences growth conemorphology by acting both as a transmembrane bridge that links extracellular netrin-1 to the actin cytoskeleton and as the core of a protein complex that directs the organization of actin. Key words: embryonic spinal commissural neuron; chemotropism; chemotropic; Axon guidance; motility; DCC; netri
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hsc70 chaperone activity underlies trio gef function in Axon growth and guidance induced by netrin 1
Journal of Cell Biology, 2015Co-Authors: Anne Debant, Jonathan Degeer, Andrew Kaplan, Pierre Mattar, Morgane Morabito, Ursula Stochaj, Timothy E Kennedy, Michel CayouetteAbstract:During development, netrin-1 is both an attractive and repulsive Axon guidance cue and mediates its attractive function through the receptor Deleted in Colorectal Cancer (DCC). The activation of Rho guanosine triphosphatases within the extending growth cone facilitates the dynamic reorganization of the cytoskeleton required to drive Axon Extension. The Rac1 guanine nucleotide exchange factor (GEF) Trio is essential for netrin-1–induced Axon outgrowth and guidance. Here, we identify the molecular chaperone heat shock cognate protein 70 (Hsc70) as a novel Trio regulator. Hsc70 dynamically associated with the N-terminal region and Rac1 GEF domain of Trio. Whereas Hsc70 expression supported Trio-dependent Rac1 activation, adenosine triphosphatase–deficient Hsc70 (D10N) abrogated Trio Rac1 GEF activity and netrin-1–induced Rac1 activation. Hsc70 was required for netrin-1–mediated Axon growth and attraction in vitro, whereas Hsc70 activity supported callosal projections and radial neuronal migration in the embryonic neocortex. These findings demonstrate that Hsc70 chaperone activity is required for Rac1 activation by Trio and this function underlies netrin-1/DCC-dependent Axon outgrowth and guidance.
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depolarization recruits dcc to the plasma membrane of embryonic cortical neurons and enhances Axon Extension in response to netrin 1
Journal of Neurochemistry, 2008Co-Authors: Katherine E Horn, Jean-francois Bouchard, Thomas Stroh, Timothy E KennedyAbstract:The netrin-1 receptor Deleted in Colorectal Cancer (DCC) is required for the formation of major Axonal projections by embryonic cortical neurons, including the corpus callosum, hippocampal commissure, and cortico-thalamic tracts. The presentation of DCC by Axonal growth cones is tightly regulated, but the mechanisms regulating DCC trafficking within neurons are not well understood. Here, we investigated the mechanisms regulating DCC recruitment to the plasma membrane of embryonic cortical neurons. In embryonic spinal commissural neurons, protein kinase A (PKA) activation recruits DCC to the plasma membrane and enhances Axon chemoattraction to netrin-1. We demonstrate that PKA activation similarly recruits DCC and increases embryonic cortical neuron Axon Extension, which, like spinal commissural neurons, respond to netrin-1 as a chemoattractant. We then determined if depolarization might recruit DCC to the plasma membrane. Neither netrin-1 induced Axon Extension, nor levels of plasma membrane DCC, were altered by depolarizing embryonic spinal commissural neurons with elevated levels of KCl. In contrast, depolarizing embryonic cortical neurons increased the amount of plasma membrane DCC, including at the growth cone, and increased Axon outgrowth evoked by netrin-1. Inhibition of PKA, phosphatidylinositol-3-kinase, protein kinase C, or exocytosis blocked the depolarization-induced recruitment of DCC and suppressed Axon outgrowth. Inhibiting protein synthesis did not affect DCC recruitment, nor were the distributions of trkB or neural cell adhesion molecule (NCAM) influenced by depolarization, consistent with selective mobilization of DCC. These findings identify a role for membrane depolarization modulating the response of Axons to netrin-1 by regulating DCC recruitment to the plasma membrane.
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deleted in colorectal cancer binding netrin 1 mediates cell substrate adhesion and recruits cdc42 rac1 pak1 and n wasp into an intracellular signaling complex that promotes growth cone expansion
The Journal of Neuroscience, 2005Co-Authors: Masoud Shekarabi, Simonw Moore, Nicolas X. Tritsch, Stephen J. Morris, Jean-francois Bouchard, Timothy E KennedyAbstract:Extracellular cues direct Axon Extension by regulating growth cone morphology. The netrin-1 receptor deleted in colorectal cancer (DCC) is required for commissural Axon Extension to the floor plate in the embryonic spinal cord. Here we demonstrate that challenging embryonic rat spinal commissural neurons with netrin-1, either in solution or as a substrate, causes DCC-dependent increases in growth cone surface area and filopodia number, which we term growth cone expansion. We provide evidence that DCC influences growth cone morphology by at least two mechanisms. First, DCC mediates an adhesive interaction with substrate-bound netrin-1. Second, netrin-1 binding to DCC recruits an intracellular signaling complex that directs the organization of actin. We show that netrin-1-induced growth cone expansion requires Cdc42 (cell division cycle 42), Rac1 (Ras-related C3 botulinum toxin substrate 1), Pak1 (p21-activated kinase), and N-WASP (neuronal Wiskott-Aldrich syndrome protein) and that the application of netrin-1 rapidly activates Cdc42, Rac1, and Pak1. Furthermore, netrin-1 recruits Cdc42, Rac1, Pak1, and N-WASP into a complex with the intracellular domain of DCC and Nck1. These findings suggest that DCC influences growth cone morphology by acting both as a transmembrane bridge that links extracellular netrin-1 to the actin cytoskeleton and as the core of a protein complex that directs the organization of actin.
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protein kinase a activation promotes plasma membrane insertion of dcc from an intracellular pool a novel mechanism regulating commissural Axon Extension
The Journal of Neuroscience, 2004Co-Authors: Jean-francois Bouchard, Masoud Shekarabi, Simonw Moore, Nicolas X. Tritsch, Philippe P Roux, Philip A Barker, Timothy E KennedyAbstract:Protein kinase A (PKA) exerts a profound influence on Axon Extension during development and regeneration; however, the molecular mechanisms underlying these effects of PKA are not understood. Here, we show that DCC (deleted in colorectal cancer), a receptor for the Axon guidance cue netrin-1, is distributed both at the plasma membrane and in a pre-existing intracellular vesicular pool in embryonic rat spinal commissural neurons. We hypothesized that the intracellular pool of DCC could be mobilized to the plasma membrane and enhance the response to netrin-1. Consistent with this, we show that application of netrin-1 causes a modest increase in cell surface DCC, without increasing the intracellular concentration of cAMP or activating PKA. Intriguingly, activation of PKA enhances the effect of netrin-1 on DCC mobilization and increases Axon Extension in response to netrin-1. PKA-dependent mobilization of DCC to the plasma membrane is selective, because the distributions of transient Axonal glycoprotein-1, neural cell adhesion molecule, and trkB are not altered by PKA in these cells. Inhibiting adenylate cyclase, PKA, or exocytosis blocks DCC translocation on PKA activation. These findings indicate that netrin-1 increases the amount of cell surface DCC, that PKA potentiates the mobilization of DCC to the neuronal plasma membrane from an intracellular vesicular store, and that translocation of DCC to the cell surface increases Axon outgrowth in response to netrin-1.
Jean-francois Bouchard - One of the best experts on this subject based on the ideXlab platform.
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Cellular/Molecular Deleted in Colorectal Cancer Binding Netrin-1 Mediates Cell Substrate Adhesion and Recruits Cdc42, Rac1, Pak1, and N-WASP into an Intracellular Signaling Complex That Promotes Growth Cone Expansion
2016Co-Authors: Masoud Shekarabi, Simonw Moore, Nicolas X. Tritsch, Stephen J. Morris, Jean-francois Bouchard, Timothy E KennedyAbstract:Extracellular cues direct Axon Extension by regulating growth conemorphology. The netrin-1 receptor deleted in colorectal cancer (DCC) is required for commissural Axon Extension to the floor plate in the embryonic spinal cord. Here we demonstrate that challenging embryonic rat spinal commissural neuronswith netrin-1, either in solution or as a substrate, causes DCC-dependent increases in growth cone surface area and filopodia number, which we term growth cone expansion. We provide evidence that DCC influences growth cone morphology by at least two mechanisms. First, DCC mediates an adhesive interaction with substrate-bound netrin-1. Second, netrin-1 binding to DCC recruits an intracellular signaling complex that directs the organization of actin. We show that netrin-1-induced growth cone expansion requires Cdc42 (cell division cycle 42), Rac1 (Ras-related C3 botulinum toxin substrate 1), Pak1 (p21-activated kinase), andN-WASP (neuronalWiskott–Aldrich syndromeprotein) and that the application of netrin-1 rapidly activates Cdc42, Rac1, andPak1. Furthermore, netrin-1 recruits Cdc42, Rac1, Pak1, and N-WASP into a complex with the intracellular domain of DCC and Nck1. These findings suggest thatDCC influences growth conemorphology by acting both as a transmembrane bridge that links extracellular netrin-1 to the actin cytoskeleton and as the core of a protein complex that directs the organization of actin. Key words: embryonic spinal commissural neuron; chemotropism; chemotropic; Axon guidance; motility; DCC; netri
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depolarization recruits dcc to the plasma membrane of embryonic cortical neurons and enhances Axon Extension in response to netrin 1
Journal of Neurochemistry, 2008Co-Authors: Katherine E Horn, Jean-francois Bouchard, Thomas Stroh, Timothy E KennedyAbstract:The netrin-1 receptor Deleted in Colorectal Cancer (DCC) is required for the formation of major Axonal projections by embryonic cortical neurons, including the corpus callosum, hippocampal commissure, and cortico-thalamic tracts. The presentation of DCC by Axonal growth cones is tightly regulated, but the mechanisms regulating DCC trafficking within neurons are not well understood. Here, we investigated the mechanisms regulating DCC recruitment to the plasma membrane of embryonic cortical neurons. In embryonic spinal commissural neurons, protein kinase A (PKA) activation recruits DCC to the plasma membrane and enhances Axon chemoattraction to netrin-1. We demonstrate that PKA activation similarly recruits DCC and increases embryonic cortical neuron Axon Extension, which, like spinal commissural neurons, respond to netrin-1 as a chemoattractant. We then determined if depolarization might recruit DCC to the plasma membrane. Neither netrin-1 induced Axon Extension, nor levels of plasma membrane DCC, were altered by depolarizing embryonic spinal commissural neurons with elevated levels of KCl. In contrast, depolarizing embryonic cortical neurons increased the amount of plasma membrane DCC, including at the growth cone, and increased Axon outgrowth evoked by netrin-1. Inhibition of PKA, phosphatidylinositol-3-kinase, protein kinase C, or exocytosis blocked the depolarization-induced recruitment of DCC and suppressed Axon outgrowth. Inhibiting protein synthesis did not affect DCC recruitment, nor were the distributions of trkB or neural cell adhesion molecule (NCAM) influenced by depolarization, consistent with selective mobilization of DCC. These findings identify a role for membrane depolarization modulating the response of Axons to netrin-1 by regulating DCC recruitment to the plasma membrane.
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deleted in colorectal cancer binding netrin 1 mediates cell substrate adhesion and recruits cdc42 rac1 pak1 and n wasp into an intracellular signaling complex that promotes growth cone expansion
The Journal of Neuroscience, 2005Co-Authors: Masoud Shekarabi, Simonw Moore, Nicolas X. Tritsch, Stephen J. Morris, Jean-francois Bouchard, Timothy E KennedyAbstract:Extracellular cues direct Axon Extension by regulating growth cone morphology. The netrin-1 receptor deleted in colorectal cancer (DCC) is required for commissural Axon Extension to the floor plate in the embryonic spinal cord. Here we demonstrate that challenging embryonic rat spinal commissural neurons with netrin-1, either in solution or as a substrate, causes DCC-dependent increases in growth cone surface area and filopodia number, which we term growth cone expansion. We provide evidence that DCC influences growth cone morphology by at least two mechanisms. First, DCC mediates an adhesive interaction with substrate-bound netrin-1. Second, netrin-1 binding to DCC recruits an intracellular signaling complex that directs the organization of actin. We show that netrin-1-induced growth cone expansion requires Cdc42 (cell division cycle 42), Rac1 (Ras-related C3 botulinum toxin substrate 1), Pak1 (p21-activated kinase), and N-WASP (neuronal Wiskott-Aldrich syndrome protein) and that the application of netrin-1 rapidly activates Cdc42, Rac1, and Pak1. Furthermore, netrin-1 recruits Cdc42, Rac1, Pak1, and N-WASP into a complex with the intracellular domain of DCC and Nck1. These findings suggest that DCC influences growth cone morphology by acting both as a transmembrane bridge that links extracellular netrin-1 to the actin cytoskeleton and as the core of a protein complex that directs the organization of actin.
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protein kinase a activation promotes plasma membrane insertion of dcc from an intracellular pool a novel mechanism regulating commissural Axon Extension
The Journal of Neuroscience, 2004Co-Authors: Jean-francois Bouchard, Masoud Shekarabi, Simonw Moore, Nicolas X. Tritsch, Philippe P Roux, Philip A Barker, Timothy E KennedyAbstract:Protein kinase A (PKA) exerts a profound influence on Axon Extension during development and regeneration; however, the molecular mechanisms underlying these effects of PKA are not understood. Here, we show that DCC (deleted in colorectal cancer), a receptor for the Axon guidance cue netrin-1, is distributed both at the plasma membrane and in a pre-existing intracellular vesicular pool in embryonic rat spinal commissural neurons. We hypothesized that the intracellular pool of DCC could be mobilized to the plasma membrane and enhance the response to netrin-1. Consistent with this, we show that application of netrin-1 causes a modest increase in cell surface DCC, without increasing the intracellular concentration of cAMP or activating PKA. Intriguingly, activation of PKA enhances the effect of netrin-1 on DCC mobilization and increases Axon Extension in response to netrin-1. PKA-dependent mobilization of DCC to the plasma membrane is selective, because the distributions of transient Axonal glycoprotein-1, neural cell adhesion molecule, and trkB are not altered by PKA in these cells. Inhibiting adenylate cyclase, PKA, or exocytosis blocks DCC translocation on PKA activation. These findings indicate that netrin-1 increases the amount of cell surface DCC, that PKA potentiates the mobilization of DCC to the neuronal plasma membrane from an intracellular vesicular store, and that translocation of DCC to the cell surface increases Axon outgrowth in response to netrin-1.
Charles A Greer - One of the best experts on this subject based on the ideXlab platform.
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odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron Axons
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Diego J Rodriguezgil, Dianna L Bartel, Austin W Jaspers, Arie S Mobley, Fumiaki Imamura, Charles A GreerAbstract:Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) Axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN Axon Extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and Axon Extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN Axons have reached the OB. Over the next 6+ days the OSN Axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN Axon adhesion and lead us to propose a new model dividing Axon Extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which Axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN Axons coalesce in glomeruli.
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Dishevelled proteins are associated with olfactory sensory neuron presynaptic terminals.
PLOS ONE, 2013Co-Authors: Diego J. Rodriguez-gil, Wilbur Hu, Charles A GreerAbstract:Olfactory sensory neurons (OSNs) project their Axons from the olfactory epithelium toward the olfactory bulb (OB) in a heterogeneous and unsorted arrangement. However, as the Axons approach the glomerular layer of the OB, Axons from OSNs expressing the same odorant receptor (OR) sort and converge to form molecularly homogeneous glomeruli. Axon guidance cues, cell adhesion molecules, and OR induced activity have been implicated in the final targeting of OSN Axons to specific glomeruli. Less understood, and often controversial, are the mechanisms used by OSN Axons to initially navigate from the OE toward the OB. We previously demonstrated a role for Wnt and Frizzled (Fz) molecules in OSN Axon Extension and organization within the olfactory nerve. Building on that we now turned our attention to the downstream signaling cascades from Wnt-Fz interactions. Dishevelled (Dvl) is a key molecule downstream of Fz receptors. Three isoforms of Dvl with specific as well as overlapping functions are found in mammals. Here, we show that Dvl-1 expression is restricted to OSNs in the dorsal recess of the nasal cavity, and labels a unique subpopulation of glomeruli. Dvl-2 and Dvl-3 have a widespread distribution in both the OE and OB. Both Dvl-1 and Dvl-2 are associated with intra-glomerular pre-synaptic OSN terminals, suggesting a role in synapse formation/stabilization. Moreover, because Dvl proteins were observed in all OSN Axons, we hypothesize that they are important determinants of OSN cell differentiation and Axon Extension.
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hyperpolarization activated cyclic nucleotide gated channels in olfactory sensory neurons regulate Axon Extension and glomerular formation
The Journal of Neuroscience, 2010Co-Authors: Arie S Mobley, Alexandra M Miller, Ricardo C Araneda, Lydia R Maurer, Frank Muller, Charles A GreerAbstract:Mechanisms influencing the development of olfactory bulb glomeruli are poorly understood. While odor receptors (ORs) play an important role in olfactory sensory neuron (OSN) Axon targeting/coalescence (Mombaerts et al., 1996; Wang et al., 1998; Feinstein and Mombaerts, 2004), recent work showed that G protein activation alone is sufficient to induce OSN Axon coalescence (Imai et al., 2006; Chesler et al., 2007), suggesting an activity-dependent mechanism in glomerular development. Consistent with these data, OSN Axon projections and convergence are perturbed in mice deficient for adenylyl cyclase III, which is downstream from the OR and catalyzes the conversion of ATP to cAMP. However, in cyclic nucleotide-gated (CNG) channel knock-out mice OSN Axons are only transiently perturbed (Lin et al., 2000), suggesting that the CNG channel may not be the sole target of cAMP. This prompted us to investigate an alternative channel, the hyperpolarization-activated, cyclic nucleotide-gated cation channel (HCN), as a potential developmental target of cAMP in OSNs. Here, we demonstrate that HCN channels are developmentally precocious in OSNs and therefore are plausible candidates for affecting OSN Axon development. Inhibition of HCN channels in dissociated OSNs significantly reduced neurite outgrowth. Moreover, in HCN1 knock-out mice the formation of glomeruli was delayed in parallel with perturbations of Axon organization in the olfactory nerve. These data support the hypothesis that the outgrowth and coalescence of OSN Axons is, at least in part, subject to activity-dependent mechanisms mediated via HCN channels.
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wnt frizzled family members mediate olfactory sensory neuron Axon Extension
The Journal of Comparative Neurology, 2008Co-Authors: Diego J Rodriguezgil, Charles A GreerAbstract:A comprehensive model has yet to emerge, but it seems likely that numerous mechanisms contribute to the specificity of olfactory sensory neuron (OSN) Axon innervation of the olfactory bulb. Elsewhere in the nervous system the Wnt/Fz family has been implicated in patterning of anterior-posterior axes, cell type specification, cell proliferation, and Axon guidance. Because of our work describing cadherin-catenin family member expression in the primary olfactory pathway, and because mechanisms of Wnt-Fz interactions can depend in part on catenins, we were encouraged to explore Wnt-Fz expression and function in OSN Axon Extension. Here, we show that OSNs express Fz-1, Fz-3, and Wnt-5a, whereas olfactory ensheathing cells (OECs) express Wnt-4. Fz-7 is also expressed in the olfactory nerve by cells that delineate large Axon fascicles, but are negative for OEC markers. Fz-1 showed a developmental downregulation. However, in adults it is expressed at different levels across the olfactory epithelium and in restricted glomeruli across the olfactory bulb, suggesting an important role in the formation and maintenance of OSN connections to the olfactory bulb. Reporter TOPGAL mice demonstrated that some OECs located in the inner olfactory nerve layer can respond to Wnt ligands. Of further interest, we show here with in vitro assays that Wnt-5a increases OSN Axon outgrowth and alters growth cone morphology. Our data point to a key role for Wnt/Fz molecules in the development of the mouse olfactory system, providing complementary mechanisms required for OSN Axon Extension and coalescence. J. Comp. Neurol. 511:301–317, 2008. © 2008 Wiley-Liss, Inc.
Andreas W. Püschel - One of the best experts on this subject based on the ideXlab platform.
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igf1r insr function is required for Axon Extension and corpus callosum formation
PLOS ONE, 2019Co-Authors: Jing Jin, Priyadarshini Ravindran, Danila Di Meo, Andreas W. PüschelAbstract:One of the earliest steps during the development of the nervous system is the establishment of neuronal polarity and the formation of an Axon. The intrinsic mechanisms that promote Axon formation have been extensively analyzed. However, much less is known about the extrinsic signals that initiate Axon formation. One of the candidates for these signals is Insulin-like growth factor 1 (Igf1) that acts through the Igf1 (Igf1R) and insulin receptors (InsR). Since Igf1R and InsR may act redundantly we analyzed conditional cortex-specific knockout mice that are deficient for both Igf1r and Insr to determine if they regulate the development of the cortex and the formation of Axons in vivo. Our results show that Igf1R/InsR function is required for the normal development of the embryonic hippocampus and cingulate cortex while the lateral cortex does not show apparent defects in the Igf1r;Insr knockout. In the cingulate cortex, the number of intermediate progenitors and deep layer neurons is reduced and the corpus callosum is absent at E17. However, cortical organization and Axon formation are not impaired in knockout embryos. In culture, cortical and hippocampal neurons from Igf1r;Insr knockout embryos extend an Axon but the length of this Axon is severely reduced. Our results indicate that Igf1R/InsR function is required for brain development in a region-specific manner and promotes Axon growth but is not essential for neuronal polarization and migration in the developing brain.
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Rnd1 regulates Axon Extension by enhancing the microtubule destabilizing activity of SCG10.
The Journal of biological chemistry, 2008Co-Authors: Sharang Ghavampur, Percy Bondallaz, Lena Will, Gabriele Grenningloh, Andreas W. PüschelAbstract:Abstract The GTPase Rnd1 affects actin dynamics antagonistically to Rho and has been implicated in the regulation of neurite outgrowth, dendrite development, and Axon guidance. Here we show that Rnd1 interacts with the microtubule regulator SCG10. This interaction requires a central domain of SCG10 comprising about 40 amino acids located within the N-terminal-half of a putative α-helical domain and is independent of phosphorylation at the four identified phosphorylation sites that regulate SCG10 activity. Rnd1 enhances the microtubule destabilizing activity of SCG10 and both proteins colocalize in neurons. Knockdown of Rnd1 or SCG10 by RNAi suppressed Axon Extension, indicating a critical role for both proteins during neuronal differentiation. Overexpression of Rnd1 in neurons induces the formation of multiple Axons. The effect of Rnd1 on Axon Extension depends on SCG10. These results indicate that SCG10 acts as an effector downstream of Rnd1 to regulate Axon Extensions by modulating microtubule organization.
Fengquan Zhou - One of the best experts on this subject based on the ideXlab platform.
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knocking out non muscle myosin ii in retinal ganglion cells promotes long distance optic nerve regeneration
bioRxiv, 2019Co-Authors: Xuewei Wang, Shuguang Yang, Chi Zhang, Y Zhang, Binbin Yang, Yi Lan Weng, Guo Li Ming, Anish R Kosanam, Fengquan ZhouAbstract:Summary In addition to changed gene expression, pathological cytoskeletal dynamics in the Axon is another key intrinsic barrier for Axon regeneration in the central nervous system (CNS). Here we showed that knocking out myosin IIA/B in retinal ganglion cells alone was sufficient to induce marked and sustained optic nerve regeneration. Combined Lin28 overexpression and myosin IIA/B knockout led to remarkable synergistic promoting effect and long-distance Axon regeneration. Immunostaining, RNA-seq and western blot analyses revealed that myosin II deletion did not affect known Axon regeneration signaling pathways or the expression of regeneration associated genes. Instead, it abolished the retraction bulb formation and significantly enhanced the Axon Extension efficiency. The study provided clear and strong evidence that directly targeting neuronal cytoskeleton was sufficient to induce strong CNS Axon regeneration, and combining gene expression in the soma and modified cytoskeletal dynamics in the Axon was an optimal approach for long-distance CNS Axon regeneration.
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gsk3 controls Axon growth via clasp mediated regulation of growth cone microtubules
Genes & Development, 2011Co-Authors: Eun Mi Hur, Byoung Dae Lee, Seong Jin Kim, Fengquan ZhouAbstract: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.
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engineering neuronal growth cones to promote Axon regeneration over inhibitory molecules
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Eun Mi Hur, In Hong Yang, Deokho Kim, Justin Byun, Philip R Nicovich, Raymond Cheong, Andre Levchenko, Nitish V Thakor, Fengquan ZhouAbstract:Neurons in the central nervous system (CNS) fail to regenerate Axons after injuries due to the diminished intrinsic Axon growth capacity of mature neurons and the hostile extrinsic environment composed of a milieu of inhibitory factors. Recent studies revealed that targeting a particular group of extracellular inhibitory factors is insufficient to trigger long-distance Axon regeneration. Instead of antagonizing the growing list of impediments, tackling a common target that mediates Axon growth inhibition offers an alternative strategy to promote Axon regeneration. Neuronal growth cone, the machinery that derives Axon Extension, is the final converging target of most, if not all, growth impediments in the CNS. In this study, we aim to promote Axon growth by directly targeting the growth cone. Here we report that pharmacological inhibition or genetic silencing of nonmuscle myosin II (NMII) markedly accelerates Axon growth over permissive and nonpermissive substrates, including major CNS inhibitors such as chondroitin sulfate proteoglycans and myelin-associated inhibitors. We find that NMII inhibition leads to the reorganization of both actin and microtubules (MTs) in the growth cone, resulting in MT reorganization that allows rapid Axon Extension over inhibitory substrates. In addition to enhancing Axon Extension, we show that local blockade of NMII activity in Axons is sufficient to trigger Axons to grow across the permissive–inhibitory border. Together, our study proposes NMII and growth cone cytoskeletal components as effective targets for promoting Axon regeneration.