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.

EphA2 Engages Git1 to Suppress Arf6 Activity Modulating Epithelial Cell–Cell Contacts

“…upon ephrinA1-Fc stimulation and colocalizes well with EphA2 ( Figure 7B). The synaptic localizing domain of Git1 was previously identified as being responsible for its localization to neuronal synapses (Zhang et al, 2003). In MDCK cells, however, we found that Git1⌬SLD-FLAG, which lacks the synaptic localizing domain, is still able to localize to cell-cell contacts, although with a lower efficiency than that of intact Git1-FLAG (Figure 7, B and C).…”

“…Git1 has been shown to localize and function at cell-cell junctions formed in neuronal synapses (Zhang et al, 2003) and immune synapses (Phee et al, 2005). However, these studies have mostly dealt with Git1 as a scaffold protein, which links cell surface receptors to the Pix-Pak pathway to remodel actin cytoskeletal architecture and stabilize these cell-cell junctions.…”

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

“…bPIX regulates formation of protrusions (14,(37)(38)(39), and overexpression of bPIX in fibroblasts and neurons alters the localization of bPIX itself, GIT1, Rac activity, and protrusions from a single leading edge to all around the cell periphery (37,39). Moreover, increased Rac activity in fibroblasts and epithelial cells correlates with multiple peripheral lamellae, or protrusions, and increased random motility (40).…”

Le complexe GIT-PIX : Une plate-forme de régulation des GTPases ARF et Rac/Cdc42

“…Par ailleurs, les protéines GIT1 semblent impliquées avec Rac et PAK dans la formation des protrusions [20]. L'implication de GIT dans la formation des synapses et la morphologie des dendrites a également été suggérée [21]. Sur le plan physiopathologique, une étude récente vient de mettre en évidence une interaction entre GIT1 et la protéine hungtingtine et a démontré la dégradation spécifique de GIT1 au cours du développement de la maladie de Huntington [22].…”