title: Synapse formation is regulated by the signaling adaptor GIT1.
abstract: Dendritic spines in the central nervous system undergo rapid actin-based shape changes, making actin regulators potential modulators of spine morphology and synapse formation. Although several potential regulators and effectors for actin organization have been identified, the mechanisms by which these molecules assemble and localize are not understood. Here we show that the G protein-coupled receptor kinase-interacting protein (GIT)1 serves such a function by targeting actin regulators and locally modulating Rac activity at synapses. In cultured hippocampal neurons, GIT1 is enriched in both pre- and postsynaptic terminals and targeted to these sites by a novel domain. Disruption of the synaptic localization of GIT1 by a dominant-negative mutant results in numerous dendritic protrusions and a significant decrease in the number of synapses and normal mushroom-shaped spines. The phenotype results from mislocalized GIT1 and its binding partner PIX, an exchange factor for Rac. In addition, constitutively active Rac shows a phenotype similar to the GIT1 mutant, whereas dominant-negative Rac inhibits the dendritic protrusion formation induced by mislocalized GIT1. These results demonstrate a novel function for GIT1 as a key regulator of spine morphology and synapse formation and point to a potential mechanism by which mutations in Rho family signaling leads to decreased neuronal connectivity and cognitive defects in nonsyndromic mental retardation.
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908-0732, USA.
authors.forename: Huaye
authors.initials: H
authors.lastname: Zhang
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Hannelore
authors.initials: H
authors.lastname: Asmussen
authors.forename: Alan F
authors.initials: AF
authors.lastname: Horwitz
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism* / Q000473:pathology; D020690:GTPase-Activating Proteins / Q000172:deficiency* / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000254:growth & development* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D010750:Phosphoproteins; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000235:genetics; D016704:Synapsins / Q000378:metabolism; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C485648:Git1 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; D064067:Rho Guanine Nucleotide Exchange Factors; D016704:Synapsins; D020744:rac GTP-Binding Proteins