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      Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

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          Abstract

          Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.

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          Most cited references127

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          Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.

          The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
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            Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.

            The actin cytoskeleton undergoes extensive remodeling during cell morphogenesis and motility. The small guanosine triphosphatase Rho regulates such remodeling, but the underlying mechanisms of this regulation remain unclear. Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM-kinase. Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction. This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK. ROCK, which is a downstream effector of Rho, did not phosphorylate cofilin directly but phosphorylated LIM-kinase, which in turn was activated to phosphorylate cofilin. Overexpression of LIM-kinase in HeLa cells induced the formation of actin stress fibers in a Y-27632-sensitive manner. These results indicate that phosphorylation of LIM-kinase by ROCK and consequently increased phosphorylation of cofilin by LIM-kinase contribute to Rho-induced reorganization of the actin cytoskeleton.
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              PTEN Deletion Enhances the Regenerative Ability of Adult Corticospinal Neurons

              Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. Here we demonstrate a critical involvement of PTEN/mTOR in controlling the regenerative capacity of mouse corticospinal neurons. Upon the completion of development, the regrowth potential of CST axons lost and this is accompanied by a down-regulation of mTOR activity in corticospinal neurons. Axonal injury further diminishes neuronal mTOR activity in these neurons. Forced up-regulation of mTOR activity in corticospinal neurons by conditional deletion of PTEN, a negative regulator of mTOR, enhances compensatory sprouting of uninjured CST axons and even more strikingly, enables successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possess the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                02 July 2020
                2020
                : 14
                : 174
                Affiliations
                [1] 1Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, PA, United States
                [2] 2Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University , Philadelphia, PA, United States
                [3] 3Department of Neurology, Lewis Katz School of Medicine at Temple University , Philadelphia, PA, United States
                Author notes

                Edited by: Tommaso Pizzorusso, University of Florence, Italy

                Reviewed by: Jerry Silver, Case Western Reserve University, United States; Melissa R. Andrews, University of Southampton, United Kingdom

                *Correspondence: Shuxin Li shuxin.li@ 123456temple.edu

                Specialty section: This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2020.00174
                7346763
                32714150
                b1c36c83-9320-4892-9f21-c97a42b35a70
                Copyright © 2020 Sami, Selzer and Li.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 March 2020
                : 22 May 2020
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 145, Pages: 12, Words: 11241
                Categories
                Cellular Neuroscience
                Review

                Neurosciences
                scar inhibition,cspg receptor,lar,ptpσ,axon regeneration,intracellular signaling,rhoa,therapeutic target

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