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Synapse formation is regulated by the signaling adaptor GIT1.

Zhang H, Webb DJ, Asmussen H, Horwitz AF - J. Cell Biol. (2003)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908-0732, USA.

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.

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GIT1 regulates synapse formation. GIT1 is targeted to synapses through the SLD. At the synapse, GIT1, or possibly other related molecules, functions as an adaptor protein recruiting exchanges factors, such as PIX, to synapses where they locally activate Rac. Locally regulated Rac activation is essential for spine morphogenesis and synapse formation. When GIT1/PIX is mislocalized from synapses, Rac is activated outside the synaptic area. Mislocalized active Rac is responsible for the increased dendritic protrusions and decreased synaptic density. Inhibition of the Rac signaling pathway results in a decrease in the density of spines and synapses. The indicated domains of GIT1 are as follows: ARF-GAP domain (ARF-GAP), ankyrin repeats (ANK), Spa2 homology domain 1 (SHD1), synaptic localization domain (SLD), and paxillin binding domain (PAX). The question mark indicates the unknown molecule that targets GIT1 to synapses.
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fig8: GIT1 regulates synapse formation. GIT1 is targeted to synapses through the SLD. At the synapse, GIT1, or possibly other related molecules, functions as an adaptor protein recruiting exchanges factors, such as PIX, to synapses where they locally activate Rac. Locally regulated Rac activation is essential for spine morphogenesis and synapse formation. When GIT1/PIX is mislocalized from synapses, Rac is activated outside the synaptic area. Mislocalized active Rac is responsible for the increased dendritic protrusions and decreased synaptic density. Inhibition of the Rac signaling pathway results in a decrease in the density of spines and synapses. The indicated domains of GIT1 are as follows: ARF-GAP domain (ARF-GAP), ankyrin repeats (ANK), Spa2 homology domain 1 (SHD1), synaptic localization domain (SLD), and paxillin binding domain (PAX). The question mark indicates the unknown molecule that targets GIT1 to synapses.

Mentions: Localized changes in the organization and dynamics of the actin cytoskeleton are thought to underlie the formation, maintenance, and plasticity of synaptic connections (Matus, 2000). Although abundant evidence points to the role of Rho family GTPases as pivotal regulators of actin dynamics and organization, the mechanisms that localize their activities to specific sites, like synapses, are not understood. Recent evidence from motile fibroblasts shows that Rac is diffusely distributed throughout the cell, whereas activated Rac is highly localized (Kraynov et al., 2000). In this study, we present evidence that the adapter protein GIT1 serves to localize Rac activity by providing a docking site for PIX, which serves as an exchange factor for Rac and a binding protein for a Rac effector, PAK. Both the recruitment of PIX to synapses and its GEF activity are necessary for the formation and stabilization of synapse-bearing spines (Fig. 8) .


Synapse formation is regulated by the signaling adaptor GIT1.

Zhang H, Webb DJ, Asmussen H, Horwitz AF - J. Cell Biol. (2003)

GIT1 regulates synapse formation. GIT1 is targeted to synapses through the SLD. At the synapse, GIT1, or possibly other related molecules, functions as an adaptor protein recruiting exchanges factors, such as PIX, to synapses where they locally activate Rac. Locally regulated Rac activation is essential for spine morphogenesis and synapse formation. When GIT1/PIX is mislocalized from synapses, Rac is activated outside the synaptic area. Mislocalized active Rac is responsible for the increased dendritic protrusions and decreased synaptic density. Inhibition of the Rac signaling pathway results in a decrease in the density of spines and synapses. The indicated domains of GIT1 are as follows: ARF-GAP domain (ARF-GAP), ankyrin repeats (ANK), Spa2 homology domain 1 (SHD1), synaptic localization domain (SLD), and paxillin binding domain (PAX). The question mark indicates the unknown molecule that targets GIT1 to synapses.
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Related In: Results  -  Collection

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fig8: GIT1 regulates synapse formation. GIT1 is targeted to synapses through the SLD. At the synapse, GIT1, or possibly other related molecules, functions as an adaptor protein recruiting exchanges factors, such as PIX, to synapses where they locally activate Rac. Locally regulated Rac activation is essential for spine morphogenesis and synapse formation. When GIT1/PIX is mislocalized from synapses, Rac is activated outside the synaptic area. Mislocalized active Rac is responsible for the increased dendritic protrusions and decreased synaptic density. Inhibition of the Rac signaling pathway results in a decrease in the density of spines and synapses. The indicated domains of GIT1 are as follows: ARF-GAP domain (ARF-GAP), ankyrin repeats (ANK), Spa2 homology domain 1 (SHD1), synaptic localization domain (SLD), and paxillin binding domain (PAX). The question mark indicates the unknown molecule that targets GIT1 to synapses.
Mentions: Localized changes in the organization and dynamics of the actin cytoskeleton are thought to underlie the formation, maintenance, and plasticity of synaptic connections (Matus, 2000). Although abundant evidence points to the role of Rho family GTPases as pivotal regulators of actin dynamics and organization, the mechanisms that localize their activities to specific sites, like synapses, are not understood. Recent evidence from motile fibroblasts shows that Rac is diffusely distributed throughout the cell, whereas activated Rac is highly localized (Kraynov et al., 2000). In this study, we present evidence that the adapter protein GIT1 serves to localize Rac activity by providing a docking site for PIX, which serves as an exchange factor for Rac and a binding protein for a Rac effector, PAK. Both the recruitment of PIX to synapses and its GEF activity are necessary for the formation and stabilization of synapse-bearing spines (Fig. 8) .

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908-0732, USA.

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.

Show MeSH
Related in: MedlinePlus