title: The RhoGEF DOCK10 is essential for dendritic spine morphogenesis.
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.
authors: Centre de Recherche en Biochimie Macromoléculaire, CNRS-UMR 5237, Université de Montpellier, 34293 Montpellier, France.
authors: Fanny
authors: F
authors: Jaudon
authors: Institute of Functional Genomics, CNRS-UMR 5203, INSERM U661, Université de Montpellier, 34094 Montpellier, France.
authors: Fabrice
authors: F
authors: Raynaud
authors: Université Pierre et Marie Curie, CNRS-UMR 7102, Université Paris 06, 75005 Paris, France.
authors: Rosine
authors: R
authors: Wehrlé
authors: Centre de Recherche en Biochimie Macromoléculaire, CNRS-UMR 5237, Université de Montpellier, 34293 Montpellier, France.
authors: Jean-Michel
authors: JM
authors: Bellanger
authors: Université Pierre et Marie Curie, CNRS-UMR 7102, Université Paris 06, 75005 Paris, France.
authors: Mohamed
authors: M
authors: Doulazmi
authors: PROTECT, Neuroprotection du cerveau en développement, UMR1141-INSERM, Université Paris-Diderot, Sorbonne Paris-Cité, 75019 Paris, France.
authors: Guilan
authors: G
authors: Vodjdani
authors: Institut des Neurosciences Cellulaires et Intégratives, CNRS-UPR 3212, Centre de Neurochimie, Université de Strasbourg, 67084 Strasbourg, France.
authors: Stéphane
authors: S
authors: Gasman
authors: Institute of Functional Genomics, CNRS-UMR 5203, INSERM U661, Université de Montpellier, 34094 Montpellier, France.
authors: Laurent
authors: L
authors: Fagni
authors: Université Pierre et Marie Curie, CNRS-UMR 7102, Université Paris 06, 75005 Paris, France.
authors: Isabelle
authors: I
authors: Dusart
authors: Centre de Recherche en Biochimie Macromoléculaire, CNRS-UMR 5237, Université de Montpellier, 34293 Montpellier, France susanne.schmidt@crbm.cnrs.fr anne.debant@crbm.cnrs.fr.
authors: Anne
authors: A
authors: Debant
authors: Centre de Recherche en Biochimie Macromoléculaire, CNRS-UMR 5237, Université de Montpellier, 34293 Montpellier, France susanne.schmidt@crbm.cnrs.fr anne.debant@crbm.cnrs.fr.
authors: Susanne
authors: S
authors: Schmidt
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000254:growth & development*; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D015398:Signal Transduction; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C581598:Cdc42 protein, mouse; C561785:DOCK10 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C515912:Pak3 protein, mouse; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein