Generation and Characterization of Rac3 Knockout Mice

Corbetta, Sara; Gualdoni, Sara; Albertinazzi, Chiara; Paris, Simona; Croci, Laura; Consalez, G. Giacomo; Curtis, Iván de

doi:10.1128/mcb.25.13.5763-5776.2005

Cited by 112 publications

(136 citation statements)

References 51 publications

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“…One potential reason for the normal polarization of the Rac1-ablated cortical neurons is that Rac3 may compensate for some Rac1-dependent functions (Bolis et al, 2003;Corbetta et al, 2009). Consistent with this view, knocking out Rac3 alone does not lead to defects in axon development (Corbetta et al, 2005;Gualdoni et al, 2007). However, downregulation of Rac1, in the Rac3-knock-out neurons, revealed changes in dendrite development and spine formation (Gualdoni et al, 2007;Corbetta et al, 2009).…”

Section: Neuronal Migration Requires Rac1 Functionsupporting

confidence: 53%

“…Rac1 and Rac3 are present in the nervous system (Didsbury et al, 1989;Bolis et al, 2003), and the expression of mutant Racs causes aberrant axon formation in mouse and chick neurons (Luo et al, 1996;Albertinazzi et al, 1998). By contrast, deletion of Rac3 or specific ablation of Rac1 in the mouse cortex does not affect axon growth (Corbetta et al, 2005;Chen et al, 2007;Gualdoni et al, 2007;Kassai et al, 2008). This suggests that axon growth may be independent of Rac activity.…”

Section: Introductionmentioning

confidence: 85%

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Rac1 Regulates Neuronal Polarization through the WAVE Complex

Tahirović¹,

Hellal²,

Neukirchen³

et al. 2010

J. Neurosci.

165

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: 53%

Section: Introductionmentioning

confidence: 85%

Rac1 Regulates Neuronal Polarization through the WAVE Complex

Tahirović¹,

Hellal²,

Neukirchen³

et al. 2010

J. Neurosci.

165

139

View full text Add to dashboard Cite

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“…However, Rac3 expression in human prostate and prostate carcinomas has not been reported yet. Unlike Rac1 knockout animals, which do not survive embryogenesis (Sugihara et al 1998), Rac3 knockout animals do survive and show no obvious developmental defects (Corbetta et al 2005). Nevertheless, Rac3 is hyperactive in breast cancers (Mira et al 2000) and recently, like Rac1, it has been implicated in the regulation of migration and invasion of ganglioblastoma and breast carcinoma cells (Chan et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Prognostic relevance of increased Rac GTPase expression in prostate carcinomas

Engers¹,

Ziegler²,

Mueller³

et al. 2007

Endocr Relat Cancer

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Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesisspecific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P!0.001) and prostate carcinomas (P!0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (nZ7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (PZ0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (PZ0.045), preoperative prostate-specific antigen levels (PZ0.044), pT stage (PZ0.002), and Gleason score (PZ0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative riskZ3.22, 95% confidence intervalZ1.04-10.00; PZ0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.

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“…Similarly, deletion of nervous system-specific Rac3 results in an increased ability for learning and coordination of skilled movements (6), deletion of the Rac-GAP ␣-Chimerin induces a hopping gait due to misguidance of corticospinal tract axons (7), and deletion of the brain-specific form of the Rac-effector Wave, which links Rac to the actin cytoskeleton, causes defects in motor coordination, learning, and memory (8).…”

mentioning

confidence: 99%

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Donald

Humby²,

Fyfe³

et al. 2008

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

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The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in motor coordination defects, but activators of Rac in the cerebellum are unknown. P-Rex family guanine-nucleotide exchange factors activate Rac. We show here that, whereas P-Rex1 expression within the brain is widespread, P-Rex2 is specifically expressed in the Purkinje neurons of the cerebellum. We have generated P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /PRex2 ؊/؊ mice, analyzed their Purkinje cell morphology, and assessed their motor functions in behavior tests. The main dendrite is thinned in Purkinje cells of P-Rex2 ؊/؊ pups and dendrite structure appears disordered in Purkinje cells of adult P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice. P-Rex2 ؊/؊ mice show a mild motor coordination defect that progressively worsens with age and is more pronounced in females than in males. P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice are ataxic, with reduced basic motor activity and abnormal posture and gait, as well as impaired motor coordination even at a young age. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function.G protein-coupled receptor ͉ guanine-nucleotide exchange factor ͉ phosphoinositide-3-kinase ͉ small GTPase Rac ͉ ataxia T he small GTPase Rac (isoforms 1, 2, and 3) controls the structure of the actomyosin cytoskeleton, gene expression, and reactive oxygen species (ROS) formation (1). In the nervous system, Rac is essential for all stages of neuronal development (neurite, axon, and dendrite formation, axon pathfinding, dendrite branching and dendritic spine formation, and survival), as shown by manipulations of Rac activity in the nervous system of animals, neuronal cell lines, and primary cultures (2).Deletion of the ubiquitous Rac1 from the mouse, whether total or specifically in the brain, is embryonic lethal (3, 4), but transgenic overexpression of constitutively active Rac1 in the Purkinje neurons of the cerebellum results in severe ataxia, with animals unable to walk in a straight line and poor performance on the rotarod (5). Similarly, deletion of nervous system-specific Rac3 results in an increased ability for learning and coordination of skilled movements (6), deletion of the Rac-GAP ␣-Chimerin induces a hopping gait due to misguidance of corticospinal tract axons (7), and deletion of the brain-specific form of the Rac-effector Wave, which links Rac to the actin cytoskeleton, causes defects in motor coordination, learning, and memory (8).Like all small GTPases, Rac is activated by guanine-nucleotide exchange factors (GEFs) (9). Several Rac-GEFs are known to control neuronal development: Tiam1/Stef regulates neurite and axon outgrowth and dendritic spine formation (2, 10); Vav2 and Vav3 control axon outgrowth from retina to thalamus (11); Trio governs neurite outgrowth, axon extension, and pathfinding (2); Kalirin regulates neurite and axon outgrowth and dendritic spine formation (2); Dock180 controls neurite ou...

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Generation and Characterization of Rac3 Knockout Mice

Cited by 112 publications

References 51 publications

Rac1 Regulates Neuronal Polarization through the WAVE Complex

Rac1 Regulates Neuronal Polarization through the WAVE Complex

Prognostic relevance of increased Rac GTPase expression in prostate carcinomas

P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

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