An Essential Role for Rac/Cdc42 GTPases in Cerebellar Granule Neuron Survival

Linseman, Daniel A.; Laessig, Tracey A.; Meintzer, Mary Kay; McClure, Maria; Barth, Holger; Aktories, Klaus; Heidenreich, Kim A.

doi:10.1074/jbc.m103959200

Cited by 76 publications

(80 citation statements)

References 56 publications

(73 reference statements)

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“…Thus, our in vivo data support previous cell culture overexpression studies (Linseman et al, 2001;Le et al, 2005) and reveal antiapoptotic effects of Rac1 signaling in the cerebellum. This particular role of Rac1 may be more widespread in the nervous system because Rac1 deficiency in the forebrain also results in an increased rate of apoptosis (Chen et al, 2009).…”

Section: Neuronal Migration Requires Rac1 Functionsupporting

confidence: 81%

Rac1 Regulates Neuronal Polarization through the WAVE Complex

Tahirović¹,

Hellal²,

Neukirchen³

et al. 2010

J. Neurosci.

171

139

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Neuronal migration and axon growth, key events during neuronal development, require distinct changes in the cytoskeleton. Although many molecular regulators of polarity have been identified and characterized, relatively little is known about their physiological role in this process. To study the physiological function of Rac1 in neuronal development, we have generated a conditional knock-out mouse, in which Rac1 is ablated in the whole brain. Rac1-deficient cerebellar granule neurons, which do not express other Rac isoforms, showed impaired neuronal migration and axon formation both in vivo and in vitro. In addition, Rac1 ablation disrupts lamellipodia formation in growth cones. The analysis of Rac1 effectors revealed the absence of the Wiskott-Aldrich syndrome protein (WASP) family verprolinhomologous protein (WAVE) complex from the plasma membrane of knock-out growth cones. Loss of WAVE function inhibited axon growth, whereas overexpression of a membrane-tethered WAVE mutant partially rescued axon growth in Rac1-knock-out neurons. In addition, pharmacological inhibition of the WAVE complex effector Arp2/3 also reduced axon growth. We propose that Rac1 recruits the WAVE complex to the plasma membrane to enable actin remodeling necessary for axon growth.

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Section: Neuronal Migration Requires Rac1 Functionsupporting

confidence: 81%

Rac1 Regulates Neuronal Polarization through the WAVE Complex

Tahirović¹,

Hellal²,

Neukirchen³

et al. 2010

J. Neurosci.

171

139

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“…In the absence of Pcdh-␥, abnormal p38 activation leads to an excessive apoptosis during development. Consistent with this hypothesis, it is well documented that p38 activation induces neuronal apoptosis (65)(66)(67)(68)(69)(70).…”

Section: Discussionsupporting

confidence: 63%

PDCD10/CCM3 Acts Downstream of γ-Protocadherins to Regulate Neuronal Survival

Lin

Meng

Zhu

et al. 2010

Journal of Biological Chemistry

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␥-Protocadherins (PCDH-␥) regulate neuronal survival in the vertebrate central nervous system. The molecular mechanisms of how PCDH-␥ mediates this function are still not understood. In this study, we show that through their common cytoplasmic domain, different PCDH-␥ isoforms interact with an intracellular adaptor protein named PDCD10 (programmed cell death 10). PDCD10 is also known as CCM3, a causative genetic defect for cerebral cavernous malformations in humans. Using RNAi-mediated knockdown, we demonstrate that PDCD10 is required for the occurrence of apoptosis upon PCDH-␥ depletion in developing chicken spinal neurons. Moreover, overexpression of PDCD10 is sufficient to induce neuronal apoptosis. Taken together, our data reveal a novel function for PDCD10/CCM3, acting as a critical regulator of neuronal survival during development.Apoptosis is essential in controlling the size of distinct neuron populations in the nervous system (1, 2). During development, 50% or more neurons undergo apoptosis to ensure the appropriate partnership of pre-and postsynaptic target cells (1,(3)(4)(5). It is well known that target-derived cues such as trophic factors and synaptic activity are critical for the survival of different neuronal populations (6 -9). Emerging evidence shows that clustered protocadherins (PCDH) 3 also play an important role in the regulation of neuronal survival (10 -13).PCDH proteins are vertebrate-specific members of the cadherin superfamily, which share significant homology in extracellular domains with cadherins but have distinct cytoplasmic domains (14 -17). Pcdh genes have a unique genomic organization in which nearly 60 Pcdh genes are tandem-arrayed in three clusters (Pcdh-␣, Pcdh-␤, and Pcdh-␥) on a single chromosome (16). Cell-specific promoter activation and allelic exclusion at the Pcdh locus generate distinct combinatorial expression patterns among individual neurons (18 -21).PCDH proteins have been shown to mediate homophilic cellcell adhesion, and they are enriched at synapses in the brain (15,(22)(23)(24). Furthermore, genetic analyses in model systems highlight the importance of PCDH function in the nervous system. These studies reveal that PCDH proteins are required for neuronal survival and synaptic connectivity in neuronal subpopulations. Deletion of Pcdh-␥ in mice leads to an increased apoptosis of spinal interneurons and retina ganglion cells and knockdown of Pcdh-␣ in zebrafish causes massive neuronal loss during neurogenesis (10 -13). Thus, clustered PCDH appears to be critical survival factors for certain neuronal populations during development. Independently from the role for survival, PCDH plays a role in the maintenance of synaptic connectivity in several neural circuits. For example, in Pcdh-␥ mutant mice, spinal interneurons and hypothalamic neurons exhibit abnormal synaptic connectivity (25, 26). Similarly, olfactory sensory neurons and serotonergic neurons have been shown to have abnormal axon projections in Pcdh-␣ mutant mice (27,28). Collectively, these data suggest th...

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“…activation) of Akt in SH-SY5Y (this report) or PC6 cells (Spencer et al, 2002a). However, mechanisms that do not depend exclusively on activation of the PI3K/Akt pathway have been described (Klocker et al, 2000;Li et al, 2000;Linseman et al, 2001). The fact that we do not observe a decrease in outgrowth in SH-SY5Y cells plated on laminin-1 may indicate that this extracellular matrix molecule either further activates basal survival pathways or potentially activates different survival pathways.…”

Section: Rit and Extracellular Matrix Interactionscontrasting

confidence: 44%

“…Candidate members of such a pathway may include novel protein kinases and/or additional members of the Ras superfamily of small GTPases. The last possibility is intriguing given that members of the Rho subfamily are necessary for neuronal outgrowth (Kuhn et al, 1998;Sebök et al, 1999;Brown et al, 2000;Linseman et al, 2001) and affect branching (Albertinazzi et al, 1998;Shen et al, 1998;Lehmann et al, 1999;Neumann et al, 2002). On the basis of our data, we suggest that Rit promotes neurite initiation through activation of the ERK pathway whereas it promotes neurite elongation and branching through an ERK-independent pathway, which may involve Rho family GTPase activation.…”

Section: Rit and Extracellular Matrix Interactionsmentioning

confidence: 58%

“…Members of the Ras and Rho subfamilies of the small GTPases are involved in mediating neuronal development and regeneration (Hagag et al, 1986;Szeberenyi et al, 1990;Qiu and Green, 1992;Kaplan and Stephens, 1994;Kuhn et al, 1998;Lehmann et al, 1999;Mazzoni et al, 1999;Sebök et al, 1999;Brown et al, 2000;Burry, 2001;Linseman et al, 2001). Rit and its most closely related proteins, Rin and RIC, constitute a branch of the Ras subfamily of small GTPases (Lee et al, 1996;Shao et al, 1999).…”

Section: Rit and Neuronal Development/regenerationmentioning

confidence: 99%

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Rit promotes MEK-independent neurite branching in human neuroblastoma cells

Hynds

Spencer

Andres

et al. 2003

Journal of Cell Science

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Rit, by sequence homology, is a member of the Ras subfamily of small guanine triphosphatases (GTPases). In PC6 cells, Rit signals through pathways both common to and different from those activated by Ras to promote cell survival and neurite outgrowth. However, the specific morphological changes induced by Rit in human cells are not known. Here, we show in a human neuronal model that Rit increases neurite outgrowth and branching through MEK-dependent and MEK-independent signaling mechanisms, respectively. Adenoviral expression of wild-type or constitutively active Rit increased neurite initiation,elongation and branching on endogenous matrix or a purified laminin-1 substratum of SH-SY5Y cells as assessed using image analysis. This outgrowth was morphologically distinct from that promoted by constitutively active Ras or Raf (evidenced by increased branching and elongation). Constitutively active Rit increased phosphorylation of ERK 1/2, but not Akt, and the MEK inhibitor PD 098059 blocked constitutively active Rit-induced neurite initiation but not elongation or branching. These results suggest that Rit plays a key role in human neuronal development and regeneration through activating both known and as yet undefined signaling pathways.

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An Essential Role for Rac/Cdc42 GTPases in Cerebellar Granule Neuron Survival

Cited by 76 publications

References 56 publications

Rac1 Regulates Neuronal Polarization through the WAVE Complex

Rac1 Regulates Neuronal Polarization through the WAVE Complex

PDCD10/CCM3 Acts Downstream of γ-Protocadherins to Regulate Neuronal Survival

Rit promotes MEK-independent neurite branching in human neuroblastoma cells

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