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J. Cell Biol. 161 (1): 131-142

Copyright © 2003 by the Rockefeller University Press.


Synapse formation is regulated by the signaling adaptor GIT1

Huaye Zhang, Donna J. Webb, Hannelore Asmussen, and Alan F. Horwitz

Department of Cell Biology, University of Virginia, Charlottesville, VA 22908

Address correspondence to Alan F. Horwitz, Dept. of Cell Biology, UVA School of Medicine, P.O. Box 800732, Charlottesville, VA 22908-0732 (for express mail add 1300 Jefferson Park Ave.). Tel.: (434) 243-6813. Fax: 434-982-3912. E-mail: horwitz{at}

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.

Key Words: synapse formation; GIT1; PIX; Rac; spine morphology

* Abbreviations used in this paper: ARF, ADP-ribosylation factor; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GIT, G protein–coupled receptor kinase–interacting protein; MR, mental retardation; PAK, p21-activated kinase; SHD, Spa2 homology domain; SLD, synaptic localization domain.

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