The Experts below are selected from a list of 6105 Experts worldwide ranked by ideXlab platform
Roman J. Giger - One of the best experts on this subject based on the ideXlab platform.
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where no synapses go gatekeepers of circuit remodeling and synaptic strength
Trends in Neurosciences, 2013Co-Authors: Yevgeniya A Mironova, Roman J. GigerAbstract:Growth inhibitory molecules in the adult mammalian central nervous system (CNS) have been implicated in the blocking of axonal sprouting and regeneration following injury. Prominent CNS regeneration inhibitors include Nogo-A, Oligodendrocyte Myelin Glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs), and a key question concerns their physiological role in the naive CNS. Emerging evidence suggests novel functions in dendrites and at synapses of glutamatergic neurons. CNS regeneration inhibitors target the neuronal actin cytoskeleton to regulate dendritic spine maturation, long-term synapse stability, and Hebbian forms of synaptic plasticity. This is accomplished in part by antagonizing plasticity-promoting signaling pathways activated by neurotrophic factors. Altered function of CNS regeneration inhibitors is associated with mental illness and loss of long-lasting memory, suggesting unexpected and novel physiological roles for these molecules in brain health.
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Oligodendrocyte Myelin Glycoprotein and nogo negatively regulate activity dependent synaptic plasticity
The Journal of Neuroscience, 2010Co-Authors: Stephen J. Raiker, Hakjoo Lee, Peter Shrager, Katherine T Baldwin, Yuntao Duan, Roman J. GigerAbstract:In the adult mammalian CNS, the growth inhibitors Oligodendrocyte-Myelin Glycoprotein (OMgp) and the reticulon RTN4 (Nogo) are broadly expressed in Oligodendrocytes and neurons. Nogo and OMgp complex with the neuronal cell surface receptors Nogo receptor-1 (NgR1) and paired Ig-like receptor-B (PirB) to regulate neuronal morphology. In the healthy CNS, NgR1 regulates dendritic spine shape and attenuates activity-driven synaptic plasticity at Schaffer collateral–CA1 synapses. Here, we examine whether Nogo and OMgp influence functional synaptic plasticity, the efficacy by which synaptic transmission occurs. In acute hippocampal slices of adult mice, Nogo-66 and OMgp suppress NMDA receptor-dependent long-term potentiation (LTP) when locally applied to Schaffer collateral–CA1 synapses. Neither Nogo-66 nor OMgp influences basal synaptic transmission or paired-pulse facilitation, a form of short-term synaptic plasticity. PirB −/− and NgR1 −/− single mutants and NgR1 −/− ; PirB −/− double mutants show normal LTP, indistinguishable from wild-type controls. In juvenile mice, LTD in NgR1 −/− , but not PirB −/− , slices is absent. Mechanistic studies revealed that Nogo-66 and OMgp suppress LTP in an NgR1 -dependent manner. OMgp inhibits LTP in part through PirB but independently of p75 . This suggests that NgR1 and PirB participate in ligand-dependent inhibition of synaptic plasticity. Loss of NgR1 leads to increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling intermediates known to regulate neuronal growth and synaptic function. In primary cortical neurons, BDNF elicited phosphorylation of AKT and p70S6 kinase is attenuated in the presence of Myelin inhibitors. Collectively, we provide evidence that mechanisms of neuronal growth inhibition and inhibition of synaptic strength are related. Thus, Myelin inhibitors and their receptors may coordinate structural and functional neuronal plasticity in CNS health and disease.
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Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008Co-Authors: Hakjoo Lee, Stephen J. Raiker, Karthik Venkatesh, Rebecca Geary, Laurie A. Robak, Yu Zhang, Hermes H. Yeh, Peter Shrager, Roman J. GigerAbstract:In the mature nervous system, changes in synaptic strength correlate with changes in neuronal structure. Members of the Nogo-66 receptor family have been implicated in regulating neuronal morphology. Nogo-66 receptor 1 (NgR1) supports binding of the Myelin inhibitors Nogo-A, MAG (Myelin-associated Glycoprotein), and OMgp (Oligodendrocyte Myelin Glycoprotein), and is important for growth cone collapse in response to acutely presented inhibitors in vitro. After injury to the corticospinal tract, NgR1 limits axon collateral sprouting but is not important for blocking long-distance regenerative growth in vivo. Here, we report on a novel interaction between NgR1 and select members of the fibroblast growth factor (FGF) family. FGF1 and FGF2 bind directly and with high affinity to NgR1 but not to NgR2 or NgR3. In primary cortical neurons, ectopic NgR1 inhibits FGF2-elicited axonal branching. Loss of NgR1 results in altered spine morphologies along apical dendrites of hippocampal CA1 neurons in vivo. Analysis of synaptosomal fractions revealed that NgR1 is enriched synaptically in the hippocampus. Physiological studies at Schaffer collateral-CA1 synapses uncovered a synaptic function for NgR1. Loss of NgR1 leads to FGF2-dependent enhancement of long-term potentiation (LTP) without altering basal synaptic transmission or short-term plasticity. NgR1 and FGF receptor 1 (FGFR1) are colocalized to synapses, and mechanistic studies revealed that FGFR kinase activity is necessary for FGF2-elicited enhancement of hippocampal LTP in NgR1 mutants. In addition, loss of NgR1 attenuates long-term depression of synaptic transmission at Schaffer collateral-CA1 synapses. Together, our findings establish that physiological NgR1 signaling regulates activity-dependent synaptic strength and uncover neuronal NgR1 as a regulator of synaptic plasticity.
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The Nogo-66 Receptor NgR1 Is Required Only for the Acute Growth Cone-Collapsing But Not the Chronic Growth-Inhibitory Actions of Myelin Inhibitors
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007Co-Authors: Onanong Chivatakarn, Shinjiro Kaneko, Marc Tessier-lavigne, Roman J. GigerAbstract:Neuronal Nogo-66 receptor 1 (NgR1) has been proposed to function as an obligatory coreceptor for the Myelin-derived ligands Nogo-A, Oligodendrocyte Myelin Glycoprotein (OMgp), and Myelin-associated Glycoprotein (MAG) to mediate neurite outgrowth inhibition by these ligands. To examine the contribution of neuronal NgR1 to outgrowth inhibition, we used two different strategies, genetic ablation of NgR1 through the germline and transient short hairpin RNA interference (shRNAi)-mediated knock-down. To monitor growth inhibition, two different paradigms were used, chronic presentation of substrate-bound inhibitor to measure neurite extension and acute application of soluble inhibitor to assay growth cone collapse. We find that regardless of the NgR1 genotype, membrane-bound MAG strongly inhibits neurite outgrowth of primary cerebellar, sensory, and cortical neurons. Similarly, substrate-bound OMgp strongly inhibits neurite outgrowth of NgR1 wild-type and mutant sensory neurons. Consistent with these results, shRNAi-mediated knock-down of neuronal NgR1 does not result in a substantial release of L-MAG (large MAG) inhibition. When applied acutely, however, MAG-Fc and OMgp-Fc induce a modest degree of growth cone collapse that is significantly attenuated in NgR1-null neurons compared with wild-type controls. Based on our findings and previous studies with Nogo-66, we propose that neuronal NgR1 has a circumscribed role in regulating cytoskeletal dynamics after acute exposure to soluble MAG, OMgp, or Nogo-66, but is not required for these ligands to mediate their growth-inhibitory properties in chronic outgrowth experiments. Our results thus provide unexpected evidence that the growth cone-collapsing activities and substrate growth-inhibitory activities of inhibitory ligands can be dissociated. We also conclude that chronic axon growth inhibition by Myelin is mediated by NgR1-independent mechanisms.
Toshihide Yamashita - One of the best experts on this subject based on the ideXlab platform.
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axon growth inhibition by rhoa rock in the central nervous system
Frontiers in Neuroscience, 2014Co-Authors: Yuki Fujita, Toshihide YamashitaAbstract:Rho kinase (ROCK) is a serine/threonine kinase and a downstream target of the small GTPase Rho. The RhoA/ROCK pathway is associated with various neuronal functions such as migration, dendrite development, and axonal extension. Evidence from animal studies reveals that RhoA/ROCK signaling is involved in various central nervous system (CNS) diseases, including optic nerve and spinal cord injuries, stroke, and neurodegenerative diseases. Given that RhoA/ROCK plays a critical role in the pathophysiology of CNS diseases, the development of therapeutic agents targeting this pathway is expected to contribute to the treatment of CNS diseases. The RhoA/ROCK pathway mediates the effects of Myelin-associated axon growth inhibitors—Nogo, Myelin-associated Glycoprotein (MAG), Oligodendrocyte-Myelin Glycoprotein (OMgp), and repulsive guidance molecule (RGM). Blocking RhoA/ROCK signaling can reverse the inhibitory effects of these molecules on axon outgrowth, and promotes axonal sprouting and functional recovery in animal models of CNS injury. To date, several RhoA/ROCK inhibitors have been under development or in clinical trials as therapeutic agents for neurological disorders. In this review, we focus on the RhoA/ROCK signaling pathway in neurological disorders. We also discuss the potential therapeutic approaches of RhoA/ROCK inhibitors for various neurological disorders.
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paired immunoglobulin like receptor b knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury
Journal of Biological Chemistry, 2011Co-Authors: Yuka Nakamura, Yuki Fujita, Masaki Ueno, Toshiyuki Takai, Toshihide YamashitaAbstract:Abstract Myelin components that inhibit axonal regeneration are believed to contribute significantly to the lack of axonal regeneration noted in the adult central nervous system. Three proteins found in Myelin, Nogo, Myelin-associated Glycoprotein, and Oligodendrocyte-Myelin Glycoprotein, inhibit neurite outgrowth in vitro. All of these proteins interact with the same receptors, namely, the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PIR-B). As per previous reports, corticospinal tract (CST) regeneration is not enhanced in NgR-knock-out mice after spinal cord injury. Therefore, we assessed CST regeneration in PIR-B-knock-out mice. We found that hindlimb motor function, as assessed using the Basso mouse scale, footprint test, inclined plane test, and beam walking test, did not differ between the PIR-B-knock-out and wild-type mice after dorsal hemisection of the spinal cord. Further, tracing of the CST fibers after injury did not reveal enhanced axonal regeneration or sprouting in the CST of the PIR-B-knock-out mice. Systemic administration of NEP1–40, a NgR antagonist, to PIR-B knock-out mice did not enhance the regenerative response. These results indicate that PIR-B knock-out is not sufficient to induce extensive axonal regeneration after spinal cord injury.
Rachel L Neve - One of the best experts on this subject based on the ideXlab platform.
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Oligodendrocyte Myelin Glycoprotein is a nogo receptor ligand that inhibits neurite outgrowth
Nature, 2002Co-Authors: Kevin C Wang, Vuk Koprivica, Jieun Kim, Rajeev Sivasankaran, Yong Guo, Rachel L NeveAbstract:The inhibitory activity associated with Myelin is a major obstacle for successful axon regeneration in the adult mammalian central nervous system (CNS)1,2. In addition to Myelin-associated Glycoprotein (MAG)3,4 and Nogo-A5,6,7, available evidence suggests the existence of additional inhibitors in CNS Myelin8. We show here that a glycosylphosphatidylinositol (GPI)-anchored CNS Myelin protein, Oligodendrocyte-Myelin Glycoprotein (OMgp), is a potent inhibitor of neurite outgrowth in cultured neurons. Like Nogo-A, OMgp contributes significantly to the inhibitory activity associated with CNS Myelin. To further elucidate the mechanisms that mediate this inhibitory activity of OMgp, we screened an expression library and identified the Nogo receptor (NgR)9 as a high-affinity OMgp-binding protein. Cleavage of NgR and other GPI-linked proteins from the cell surface renders axons of dorsal root ganglia insensitive to OMgp. Introduction of exogenous NgR confers OMgp responsiveness to otherwise insensitive neurons. Thus, OMgp is an important inhibitor of neurite outgrowth that acts through NgR and its associated receptor complex. Interfering with the OMgp/NgR pathway may allow lesioned axons to regenerate after injury in vivo.
Jane K. Relton - One of the best experts on this subject based on the ideXlab platform.
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lingo 1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury
Molecular and Cellular Neuroscience, 2006Co-Authors: Leungwah Yick, Xinhua Lee, Zhaohui Shao, Joy Wang, John M Mccoy, Blake R Pepinsky, Jane K. ReltonAbstract:LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, Myelin-associated Glycoprotein (MAG) and Oligodendrocyte-Myelin Glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased Oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.
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lingo 1 is a component of the nogo 66 receptor p75 signaling complex
Nature Neuroscience, 2004Co-Authors: Xinhua Lee, Zhaohui Shao, Greg Thill, Jane K. Relton, Melissa Levesque, Norm Allaire, Steve Perrin, Bryan Sands, Thomas Crowell, Richard L CateAbstract:Axon regeneration in the adult CNS is prevented by inhibitors in Myelin. These inhibitors seem to modulate RhoA activity by binding to a receptor complex comprising a ligand-binding subunit (the Nogo-66 receptor NgR1) and a signal transducing subunit (the neurotrophin receptor p75). However, in reconstituted non-neuronal systems, NgR1 and p75 together are unable to activate RhoA, suggesting that additional components of the receptor may exist. Here we describe LINGO-1, a nervous system-specific transmembrane protein that binds NgR1 and p75 and that is an additional functional component of the NgR1/p75 signaling complex. In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to Oligodendrocyte Myelin Glycoprotein, as measured by RhoA activation. A dominant-negative human LINGO-1 construct attenuated Myelin inhibition in transfected primary neuronal cultures. This effect on neurons was mimicked using an exogenously added human LINGO-1-Fc fusion protein. Together these observations suggest that LINGO-1 has an important role in CNS biology.
Courtney Williamson - One of the best experts on this subject based on the ideXlab platform.
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neuregulin 1 type iii improves peripheral nerve Myelination in a mouse model of congenital hypoMyelinating neuropathy
Human Molecular Genetics, 2019Co-Authors: Francesca Ornaghi, Ghjuvanghjacumu Shackleford, Jie Wang, Cristina Scapin, Camila Lopezanido, Nicholas Silvestri, Neil M Robertson, Sophie Belin, Courtney WilliamsonAbstract:Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along Myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and Myelination. Here we ask if modulating NRG1 type III levels in neurons would restore Myelination in a model of congenital hypoMyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the Myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential Myelin genes. Rather, we observed the activation of MAPK/ERK and other Myelin genes such as peripheral Myelin protein 2 and Oligodendrocyte Myelin Glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on Myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves Myelination defects during development in a model of CHN.
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neuregulin 1 type iii reduces severity in a mouse model of congenital hypoMyelinating neuropathy
bioRxiv, 2018Co-Authors: Belin Sophie, Francesca Ornaghi, Ghjuvanghjacumu Shackleford, Jie Wang, Cristina Scapin, Camila Lopezanido, Nicholas Silvestri, Neil M Robertson, Courtney Williamson, Akihiro IshiiAbstract:Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along Myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and Myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore Myelination in a model of congenital hypoMyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the Myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential Myelin genes. Rather, we observed the activation of MAPK/ERK and other Myelin genes such as peripheral Myelin protein 2 (Pmp2) and Oligodendrocyte Myelin Glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on Myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores Myelination defects during development in a model of CHN.
