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      The RhoGEF DOCK10 is essential for dendritic spine morphogenesis

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          Abstract

          Rho GTPases are crucial regulators of dendritic spine morphogenesis. However, a clear picture of the RhoGEFs activating Rho GTPases during this process is lacking. Gene expression profiling of purified Purkinje cells is used to identify the RhoGEF DOCK10 as essential for spine morphogenesis, activating a Cdc42-mediated pathway.

          Abstract

          By regulating actin cytoskeleton dynamics, Rho GTPases and their activators RhoGEFs are implicated in various aspects of neuronal differentiation, including dendritogenesis and synaptogenesis. Purkinje cells (PCs) of the cerebellum, by developing spectacular dendrites covered with spines, represent an attractive model system in which to decipher the molecular signaling underlying these processes. To identify novel regulators of dendritic spine morphogenesis among members of the poorly characterized DOCK family of RhoGEFs, we performed gene expression profiling of fluorescence-activated cell sorting (FACS)-purified murine PCs at various stages of their postnatal differentiation. We found a strong increase in the expression of the Cdc42-specific GEF DOCK10. Depleting DOCK10 in organotypic cerebellar cultures resulted in dramatic dendritic spine defects in PCs. Accordingly, in mouse hippocampal neurons, depletion of DOCK10 or expression of a DOCK10 GEF-dead mutant led to a strong decrease in spine density and size. Conversely, overexpression of DOCK10 led to increased spine formation. We show that DOCK10 function in spinogenesis is mediated mainly by Cdc42 and its downstream effectors N-WASP and PAK3, although DOCK10 is also able to activate Rac1. Our global approach thus identifies an unprecedented function for DOCK10 as a novel regulator of dendritic spine morphogenesis via a Cdc42-mediated pathway.

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          Most cited references41

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          The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly.

          Although small GTP-binding proteins of the Rho family have been implicated in signaling to the actin cytoskeleton, the exact nature of the linkage has remained obscure. We describe a novel mechanism that links one Rho family member, Cdc42, to actin polymerization. N-WASP, a ubiquitously expressed Cdc42-interacting protein, is required for Cdc42-stimulated actin polymerization in Xenopus egg extracts. The C terminus of N-WASP binds to the Arp2/3 complex and dramatically stimulates its ability to nucleate actin polymerization. Although full-length N-WASP is less effective, its activity can be greatly enhanced by Cdc42 and phosphatidylinositol (4,5) bisphosphate. Therefore, N-WASP and the Arp2/3 complex comprise a core mechanism that directly connects signal transduction pathways to the stimulation of actin polymerization.
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            The role of the Rho GTPases in neuronal development.

            Our brain serves as a center for cognitive function and neurons within the brain relay and store information about our surroundings and experiences. Modulation of this complex neuronal circuitry allows us to process that information and respond appropriately. Proper development of neurons is therefore vital to the mental health of an individual, and perturbations in their signaling or morphology are likely to result in cognitive impairment. The development of a neuron requires a series of steps that begins with migration from its birth place and initiation of process outgrowth, and ultimately leads to differentiation and the formation of connections that allow it to communicate with appropriate targets. Over the past several years, it has become clear that the Rho family of GTPases and related molecules play an important role in various aspects of neuronal development, including neurite outgrowth and differentiation, axon pathfinding, and dendritic spine formation and maintenance. Given the importance of these molecules in these processes, it is therefore not surprising that mutations in genes encoding a number of regulators and effectors of the Rho GTPases have been associated with human neurological diseases. This review will focus on the role of the Rho GTPases and their associated signaling molecules throughout neuronal development and discuss how perturbations in Rho GTPase signaling may lead to cognitive disorders.
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              Molecular mechanisms of dendritic spine morphogenesis.

              Excitatory synapses are formed on dendritic spines, postsynaptic structures that change during development and in response to synaptic activity. Once mature, however, spines can remain stable for many months. The molecular mechanisms that control the formation and elimination, motility and stability, and size and shape of dendritic spines are being revealed. Multiple signaling pathways, particularly those involving Rho and Ras family small GTPases, converge on the actin cytoskeleton to regulate spine morphology and dynamics bidirectionally. Numerous cell surface receptors, scaffold proteins and actin binding proteins are concentrated in spines and engaged in spine morphogenesis.
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                Author and article information

                Contributors
                Role: Monitoring Editor
                Journal
                Mol Biol Cell
                Mol. Biol. Cell
                molbiolcell
                mbc
                Mol. Bio. Cell
                Molecular Biology of the Cell
                The American Society for Cell Biology
                1059-1524
                1939-4586
                01 June 2015
                : 26
                : 11
                : 2112-2127
                Affiliations
                [1] aCentre de Recherche en Biochimie Macromoléculaire, CNRS-UMR 5237, Université de Montpellier, 34293 Montpellier, France
                [2] bInstitute of Functional Genomics, CNRS-UMR 5203, INSERM U661, Université de Montpellier, 34094 Montpellier, France
                [3] cUniversité Pierre et Marie Curie, CNRS-UMR 7102, Université Paris 06, 75005 Paris, France
                [4] dPROTECT, Neuroprotection du cerveau en développement, UMR1141-INSERM, Université Paris-Diderot, Sorbonne Paris-Cité, 75019 Paris, France
                [5] eInstitut des Neurosciences Cellulaires et Intégratives, CNRS-UPR 3212, Centre de Neurochimie, Université de Strasbourg, 67084 Strasbourg, France
                Nagoya University
                Author notes
                Address correspondence to: Susanne Schmidt ( susanne.schmidt@ 123456crbm.cnrs.fr ), Anne Debant ( anne.debant@ 123456crbm.cnrs.fr ).
                Article
                E14-08-1310
                10.1091/mbc.E14-08-1310
                4472020
                25851601
                5a4c8a7c-5a45-46c7-abc1-111d70ed69e4
                © 2015 Jaudon et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( http://creativecommons.org/licenses/by-nc-sa/3.0).

                “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.

                History
                : 21 August 2014
                : 31 March 2015
                : 02 April 2015
                Categories
                Articles
                Signaling

                Molecular biology
                Molecular biology

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