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      Integrins promote axonal regeneration after injury of the nervous system

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          ABSTRACT

          Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system.

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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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            Integrin ligands at a glance.

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              Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo.

              Within the vertebrate nervous system, the presence of many different lineages of neurons and glia complicates the molecular characterization of single neuronal populations. In order to elucidate molecular mechanisms underlying the specification and development of corticospinal motor neurons (CSMN), we purified CSMN at distinct stages of development in vivo and compared their gene expression to two other pure populations of cortical projection neurons: callosal projection neurons and corticotectal projection neurons. We found genes that are potentially instructive for CSMN development, as well as genes that are excluded from CSMN and are restricted to other populations of neurons, even within the same cortical layer. Loss-of-function experiments in null mutant mice for Ctip2 (also known as Bcl11b), one of the newly characterized genes, demonstrate that it plays a critical role in the development of CSMN axonal projections to the spinal cord in vivo, confirming that we identified central genetic determinants of the CSMN population.
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                Author and article information

                Contributors
                bn246@cam.ac.uk
                jf108@cam.ac.uk
                Journal
                Biol Rev Camb Philos Soc
                Biol Rev Camb Philos Soc
                10.1111/(ISSN)1469-185X
                BRV
                Biological Reviews of the Cambridge Philosophical Society
                Blackwell Publishing Ltd (Oxford, UK )
                1464-7931
                1469-185X
                15 February 2018
                August 2018
                : 93
                : 3 ( doiID: 10.1111/brv.2018.93.issue-3 )
                : 1339-1362
                Affiliations
                [ 1 ] John van Geest Centre for Brain Repair, Department of Clinical Neurosciences University of Cambridge Cambridge CB2 0PY U.K.
                [ 2 ] Laboratory for Regeneration of Sensorimotor Systems Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW) 1105 BA Amsterdam The Netherlands
                [ 3 ] Biological Sciences University of Southampton Southampton SO17 1BJ U.K.
                [ 4 ] Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience Vrije Universiteit Amsterdam 1081 HV Amsterdam The Netherlands
                [ 5 ] Centre of Reconstructive Neuroscience Institute of Experimental Medicine 142 20 Prague 4 Czech Republic
                Author notes
                [*] [* ] Address for correspondence (Bart Nieuwenhuis – Tel: +44 1223 331160; E‐mail: bn246@ 123456cam.ac.uk ; James W. Fawcett – Tel: +44 1223 331160; E‐mail: jf108@ 123456cam.ac.uk )
                Author information
                http://orcid.org/0000-0002-2065-2271
                http://orcid.org/0000-0001-5144-534X
                http://orcid.org/0000-0001-5960-5619
                http://orcid.org/0000-0002-8341-1096
                http://orcid.org/0000-0002-7990-4568
                Article
                BRV12398
                10.1111/brv.12398
                6055631
                29446228
                ef96bb56-b916-498f-a9f7-f0d314a4d2be
                © 2018 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 07 July 2017
                : 23 December 2017
                : 11 January 2018
                Page count
                Figures: 4, Tables: 6, Pages: 24, Words: 22900
                Funding
                Funded by: International Spinal Research Trust
                Award ID: NRB110
                Funded by: ERA‐NET NEURON
                Award ID: 013‐16‐002
                Funded by: Medical Research Council
                Award ID: G1000864
                Funded by: Hersenstichting
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                brv12398
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:23.07.2018

                Ecology
                axon regeneration,integrin,kindlin,receptor activation state,selective polarised transport,traumatic injury of the nervous system

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