Role of the Rho GTPase‐activating protein RICS in neurite outgrowth

Nasu‐Nishimura, Yukiko; Hayashi, Tomoatsu; Ohishi, Tomohiro; Okabe, Tetsuro; Ohwada, Susumu; Hasegawa, Yoshimi; Senda, Toshiya; Toyoshima, Chikashi; Nakamura, Tsutomu; Akiyama, Tetsu

doi:10.1111/j.1365-2443.2006.00966.x

Cited by 43 publications

(35 citation statements)

References 26 publications

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“…We focused on p250GAP because it was the only predicted miR132 target that showed perfect conservation across the vertebrate phylum. In vivo pull-down assays suggest that p250GAP potentially regulates several Rho family GTPases (16)(17)(18)(19)(20), and cerebellar granule cells from p250GAP-knockout mice show increased Cdc42 activity (18). p250GAP is enriched in the postsynaptic density where it interacts with the NMDA NR2B receptor subunit and the scaffold protein PSD-95 (25,26).…”

Section: Discussionmentioning

confidence: 99%

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An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

Wayman

Davare

Ando³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

506

461

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Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synapse growth and plasticity remain largely uncharacterized. Here, we show that microRNA 132 (miR132) is an activity-dependent rapid response gene regulated by the cAMP response element-binding (CREB) protein pathway. Introduction of miR132 into hippocampal neurons enhanced dendrite morphogenesis whereas inhibition of miR132 by 2 O-methyl RNA antagonists blocked these effects. Furthermore, neuronal activity inhibited translation of p250GAP, a miR132 target, and siRNA-mediated knockdown of p250GAP mimicked miR132-induced dendrite growth. Experiments using dominant-interfering mutants suggested that Rac signaling is downstream of miR132 and p250GAP. We propose that the miR132-p250GAP pathway plays a key role in activity-dependent structural and functional plasticity.cAMP response element-binding (CREB) protein ͉ transcription ͉ CaM kinase ͉ actin cytoskeleton ͉ Rac N euronal activity regulates the development and modification of neuronal circuitry in part by activating genetic programs. Activity-regulated gene expression has been implicated in axon guidance, dendrite elaboration, synapse formation, and long-lasting synaptic plasticity (1, 2). Dendrites are the primary site of excitatory synapses, and their morphogenesis determines both the size and number of synaptic contacts (3). Although dendritic development is partly controlled by intrinsic factors, neuronal activity also plays a critical role. Indeed, the timing of afferent innervation and synapse formation coincides with the period of maximum growth and dendritic remodeling (3).The transcription factor cAMP response element-binding (CREB) protein is a key regulator of dendritic growth (4) and activity-regulated dendritic refinement in mature neurons (5). Although CREB is believed to be a critical regulator of neuronal plasticity, few CREB targets have been directly linked to plasticity. To identify these genes, we developed a novel technology, termed serial analysis of chromatin occupancy (SACO) that facilitated the genome-wide identification of CREB target regions (6). We focused on microRNAs (miRNAs) because the ability of these molecules to repress gene expression is believed to play an important role in development, differentiation, proliferation, survival, and oncogenesis (7). Interestingly, a significant fraction of miRNAs are enriched or specifically expressed in the nervous system (8), and transcription of some miRNAs changes dynamically during brain development (9, 10). miRNAs have been implicated in development of neuronal asymmetry in Caenorhabditis elegans, maturation of sensory neurons in Drosophila, and neurite outgrowth and spine homeostasis in rodents (11)(12)(13)(14). Although activity is believed to play an essential role in sculpting neuronal development, miRNAs induced by neuronal activity have not been described.Here, we show that microRNA 132 (miR132) is an a...

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Section: Discussionmentioning

confidence: 99%

“…p250GAP has been reported to inhibit Rho family GTPases in vitro (16)(17)(18)(19)(20). To determine which Rho family GTPases participate in miR132-and p250GAP-regulated dendritic growth, we used dominant-interfering mutants.…”

Section: Activity Regulates Dendritic Growth Via Mir132 Inhibition Ofmentioning

confidence: 99%

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

Wayman

Davare

Ando³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

506

461

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“…RICS is expressed predominantly in neurons of the brain and involved in neurite extension at the growth cones and presumably N-methyl-D-aspartate (NMDA) signaling at the post-synaptic density (PSD), where it forms a complex with ␤-catenin, N-cadherin, NMDA receptors, and PSD-95 Nasu-Nishimura et al 2006). Recently, we identified a splicing variant of RICS, termed PX-RICS, which is expressed in a wide variety of tissues and cell lines (Hayashi et al 2007).…”

mentioning

confidence: 99%

PX-RICS mediates ER-to-Golgi transport of the N-cadherin/β-catenin complex

Nakamura¹,

Hayashi²,

Nasu‐Nishimura³

et al. 2008

Genes Dev.

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“…Coomassie Blue staining shows the GST fusions used in the pull-down assay. studies of p200 in mice suggest that deletion of p200 causes an up-regulation of Cdc42 activity in the neuron (35). Under overexpression conditions in NIH 3T3 cells, we found that p200 was an active GAP in down-regulating RhoA-GTP and Cdc42-GTP formation, whereas p200 R58K was inactive toward Cdc42 or RhoA (Fig.…”

Section: P200 Rhogap-induced Cellular Transformation Requires Both Thmentioning

confidence: 74%

p200 RhoGAP Promotes Cell Proliferation by Mediating Cross-talk between Ras and Rho Signaling Pathways

Shang

Moon

Zheng

2007

Journal of Biological Chemistry

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p200 RhoGAP, a member of the Rho GTPase-activating protein (RhoGAP) family, was previously implicated in the regulation of neurite outgrowth through its RhoGAP activity. Here we show that ectopic expression of p200 RhoGAP stimulates fibroblast cell proliferation and cell cycle progression, leading to transformation. The morphology of the foci induced by p200 RhoGAP is distinct from that formed by Rac or Rho activation but similar to that induced by oncogenic Ras, raising the possibility that p200 RhoGAP may engage Ras signaling. Expression of p200 RhoGAP results in a significant increase of Ras-GTP and the activation of two downstream signaling pathways of Ras, ERK1/2 and phosphatidylinositol 3-kinase. Inhibition of Ras or ERK1/2, but not phosphatidylinositol 3-kinase, effectively suppresses the foci formation induced by p200 RhoGAP, suggesting that the Ras-ERK pathway is required for p200 RhoGAP-mediated cell transformation. p200 RhoGAP co-localizes with p120 RasGAP in cells and forms a complex with p120 RasGAP, and this interaction is mediated by the C-terminal region and the Src homology 3 domain of p200 RhoGAP and p120 RasGAP, respectively. Mutations of p200 RhoGAP that disrupt interaction with p120 RasGAP abolish its Ras activation and cell transforming activities. Interestingly, the RhoGAP activity of the N-terminal RhoGAP domain in p200 RhoGAP is also required for its full transforming activity, and expression of a dominant negative RhoA mutant that blocks RhoA cycling between the GDP-and GTP-bound states suppresses p200 RhoGAP transformation. These results suggest that a Rho GTPase-activating protein may have a positive input to cell proliferation and provide evidence that p200 RhoGAP can mediate cross-talks between Ras-and Rho-regulated signaling pathways in cell growth regulation.

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Role of the Rho GTPase‐activating protein RICS in neurite outgrowth

Cited by 43 publications

References 26 publications

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP

PX-RICS mediates ER-to-Golgi transport of the N-cadherin/β-catenin complex

p200 RhoGAP Promotes Cell Proliferation by Mediating Cross-talk between Ras and Rho Signaling Pathways

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