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The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain.

ABSTRACT: Progenitor cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing forebrain give rise to neurons and glial cells, and are characterized by distinct morphologies and proliferative behaviors. The mechanisms that distinguish VZ and SVZ progenitors are not well understood, although the homeodomain transcription factor Cux2 and Cyclin D2, a core component of the cell cycle machinery, are specifically involved in controlling SVZ cell proliferation. Rho GTPases have been implicated in regulating the proliferation, differentiation, and migration of many cell types, and one family member, Cdc42, affects the polarity and proliferation of radial glial cells in the VZ. Here, we show that another family member, Rac1, is required for the normal proliferation and differentiation of SVZ progenitors and for survival of both VZ and SVZ progenitors. A forebrain-specific loss of Rac1 leads to an SVZ-specific reduction in proliferation, a concomitant increase in cell cycle exit, and premature differentiation. In Rac1 mutants, the SVZ and VZ can no longer be delineated, but rather fuse to become a single compact zone of intermingled cells. Cyclin D2 expression, which is normally expressed by both VZ and SVZ progenitors, is reduced in Rac1 mutants, suggesting that the mutant cells differentiate precociously. Rac1-deficient mice can still generate SVZ-derived upper layer neurons, indicating that Rac1 is not required for the acquisition of upper layer neuronal fates, but instead is needed for the normal regulation of proliferation by progenitor cells in the SVZ.

SUBMITTER: Leone DP

PROVIDER: S-EPMC2929936 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain.

Leone Dino P DP Srinivasan Karpagam K Brakebusch Cord C McConnell Susan K SK

Developmental neurobiology 20100801 9

Progenitor cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing forebrain give rise to neurons and glial cells, and are characterized by distinct morphologies and proliferative behaviors. The mechanisms that distinguish VZ and SVZ progenitors are not well understood, although the homeodomain transcription factor Cux2 and Cyclin D2, a core component of the cell cycle machinery, are specifically involved in controlling SVZ cell proliferation. Rho GTPases have been imp ...[more]

PMID: 20506362

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Project description:The Plexin family of transmembrane receptors are unique in that their intracellular region interacts directly with small GTPases of the Rho family. The Rho GTPase binding domain of plexin (RBD)-which is responsible for these interactions-can bind with Rac1 as well as Rnd1 GTPases. GTPase complexes have been crystallized with the RBDs of plexinA1, -A2, and -B1. The protein association is thought to elicit different functional responses in a GTPase and plexin isoform specific manner, but the origin of this is unknown. In this project, we investigated complexes between several RBD and Rac1/Rnd1 GTPases using multimicrosecond length all atom molecular dynamics simulations, also with reference to the free forms of the RBDs and GTPases. In accord with the crystallographic data, the RBDs experience more structural changes than Rho-GTPases upon complex formation. Changes in protein dynamics and networks of correlated motions are revealed by analyzing dihedral angle fluctuations in the proteins. The extent of these changes differs between the different RBDs and also between the Rac1 and Rnd1 GTPases. While the RBDs in the free and bound states have similar-if not decreased-correlations, correlations within the GTPases are increased upon binding. Mapping highly correlated residues to the structures, it is found that the plexinA1, -B1, and -A2 RBDs all have similar communication pathways within the ubiquitin fold, but that different residues are involved. Dynamic network analyses indicate that plexinA1 and -B1 RBDs interact with small GTPases in a similar manner, whereas complexes with the plexinA2 RBD display different features. Importantly complexes with Rnd1 have a considerable number of dynamic correlations and network connections between the proteins, whereas such features are missing in the RBD-Rac1 complexes. Overall, the simulations suggest mechanisms that are consistent with the experimental data on plexinB1 and indicate RBD and GTPase isoform specific changes in protein dynamics upon complex formation.

Dataset Information

The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain.

Publications

The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain.

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