Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines

Luo, Liqun; Hensch, Takao K.; Ackerman, Larry; Barbel, Sandra; Jan, Yuh Nung

doi:10.1038/379837a0

Cited by 437 publications

(336 citation statements)

References 26 publications

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“…7B,D). This result is also in line with previous studies that ectopic expression of the constitutively active form of Rac1 promotes dendritic branching (Luo et al, 1996;Threadgill et al, 1997;Ruchhoeft et al, 1999;Li et al, 2000). The enhanced dendritic branching caused by Rac1 overexpression is much more dramatic than that caused by Fmr1 loss-of-function, and this is presumably due to the high level of ectopic expression of Rac1.…”

Section: Overexpression Of Rac1 In Da Neurons Causes Increased Dendrisupporting

confidence: 81%

Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

et al. 2003

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Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 gene. How these mutations affect neuronal development and function remains largely elusive. We generated specific point mutations or small deletions in the Drosophila fragile X-related (Fmr1) gene and examined the roles of Fmr1 in dendritic development of dendritic arborization (DA) neurons in Drosophila larvae. We found that Fmr1 could be detected in the cell bodies and proximal dendrites of DA neurons and that Fmr1loss-of-function mutations increased the number of higher-order dendritic branches. Conversely, overexpression of Fmr1 in DA neurons dramatically decreased dendritic branching. In dissecting the mechanisms underlying Fmr1 function in dendrite development, we found that the mRNA encoding small GTPase Rac1 was present in the Fmr1-messenger ribonucleoprotein complexes in vivo. Mosaic analysis with a repressor cell marker (MARCM) and overexpression studies revealed that Rac1 has a cell-autonomous function in promoting dendritic branching of DA neurons. Furthermore, Fmr1 and Rac1 genetically interact with each other in controlling the formation of fine dendritic branches. These findings demonstrate that Fmr1 affects dendritic development and that Rac1 is partially responsible for mediating this effect.

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Section: Overexpression Of Rac1 In Da Neurons Causes Increased Dendrisupporting

confidence: 81%

Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

et al. 2003

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“…Nck can bind via its SH2 domain to the Eph receptor, which is known to play a role in axon guidance (Holland et al, 1997;Stein et al, 1998). Rac has also been shown to be involved in axon outgrowth in Drosophila and in mice (Luo et al, 1994(Luo et al, , 1996. It seems likely that Nck plays a role in integrating information from spatial gradients of tyrosine phosphorylated receptors and GTP-bound Rho-family GTPases at the growth cone.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of activation of Pak1 kinase by membrane localization

Mayer

1999

Oncogene

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Pak kinases are a family of serine/threonine protein kinases homologous to Ste20p of yeast. Paks can be activated in vivo and in vitro by binding to GTP-bound Cdc42 and Rac1, members of the Rho family of small GTPases implicated in regulating the organization of the actin cytoskeleton. We have previously reported that the SH2/SH3-containing adaptor protein Nck binds Pak kinase through its second SH3 domain. Pak1 can be targeted to the membrane by Nck in response to tyrosine phosphorylation, and membrane association of Pak1 is su cient to increase its speci®c activity. The mechanism whereby Pak is activated by membrane localization, however, is unknown. We show here that expression of three proteins that inhibit Rho-family GTPases by di erent mechanisms (RhoGDI, Bcr and D57Y Cdc42) all block the activation of Pak by a membrane-targeted Nck SH3 domain, demonstrating that the in vivo activation of Pak1 induced by membrane localization is dependent on Rho-family GTPases. This implies that Pak activity can be regulated in cells both by the level of GTP loading of various Rho-family GTPases and the local concentration of Pak relative to these GTPases. Our data also suggest the existence of Rho-family GTPases in addition to Cdc42 and Rac1 that can activate Pak on membranes.

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“…Neurotrophins initiate two different signaling cascades for survival and axonal differentiation (for reviews, see . There is compelling evidence that Rac activity is involved in the dynamics of axonal and dendritic differentiation (Luo et al, 1996;Threadgill et al, 1997;Ruchuoeft et al, 1999;Li et al, 2000;Nakayama et al, 2000, Tashiro et al, 2000). Here we demonstrate that Rac activity is also required for axonal responses of TG cells to neurotrophic factors.…”

Section: Rac and Rho Regulate Neurotrophin-induced Trigeminal Axon Oumentioning

confidence: 99%

“…Relative abundance of active Rho and Rac might regulate growth cone behavior during axon navigation (Mueller, 1999). Dominant negative and constitutively active versions of Rho GTPases have been used to study their role in axonal arborization (Threadgill et al, 1997;Nakayama et al, 2000), dendritic growth (Threadgill et al, 1997;Ruchoeft et al, 1999;Nakayama et al, 2000;Li et al, 2000), neuronal remodeling (Luo et al, 1996;Ruchoeft et al, 1999;Li et al, 2000), and growth cone motility (Jin and Strittmatter, 1997;Kozma et al, 1997;Ruckhoeft et al, 1999;Kuhn et al, 2000;Nakayama et al, 2000: Wahl et al, 2000. Dominant negative proteins bind irreversibly to the specific GEF molecules, which mediate the exchange of GDP to GTP and compete for the activation of endogenous small GTPases inside the cell.…”

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confidence: 99%

Regulation of neurotrophin‐induced axonal responses via Rho GTPases

Özdinler

Erzurumlu

2001

J of Comparative Neurology

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Nerve growth factor (NGF) and related neurotrophins induce differential axon growth patterns from embryonic sensory neurons. In wholemount explant cultures of embryonic rat trigeminal ganglion and brainstem or in dissociated cell cultures of the trigeminal ganglion, exogenous supply of NGF leads to axonal elongation, whereas neurotrophin-3 (NT-3) treatment leads to short branching and arborization. Axonal responses to neurotrophins might be mediated via the Rho GTPases. To investigate this possibility, we prepared wholemount trigeminal pathway cultures from E15 rats. We infected the ganglia with recombinant vaccinia viruses that express GFP-tagged dominant negative Rac, Rho, or constitutively active Rac or treated the cultures with lysophosphatitic acid (LPA) to activate Rho. We then examined axonal responses to NGF by use of the lipophilic tracer DiI. Rac activity induced longer axonal growth from the central trigeminal tract, whereas the dominant negative construct of Rac eliminated NGF-induced axon outgrowth. Rho activity also significantly reduced, and the Rho dominant negative construct increased, axon growth from the trigeminal tract. Similar alterations in axonal responses to NT-3 and brainderived neurotrophic factor were also noted. Our results demonstrate that Rho GTPases play a major role in neurotrophin-induced axonal differentiation of embryonic trigeminal axons. KeywordsRac; Rho; trigeminal axon growth; NGF; BDNF; viral vectors Primary sensory neurons of the dorsal root and trigeminal (TG) ganglia depend on targetreleased neurotrophins for survival and express specific Trk receptors (McMahon et al., 1994;Wright and Snider, 1995;Conover and Yancopoulos, 1997;Davies, 1997, Davies, 1998Enokido et al., 1999;Huang et al., 1999b). Recent studies also suggest that neurotrophins play a major role in axonal differentiation (Hoyle et al., 1993;Lentz et al., 1999;Ulupinar et al., 2000a; see also Gallo and Letourneau, 2000, for a review). During axonal development, elongation and retraction of growth cones are all related to the arrangement of actin cytoskeleton (for reviews, see Lin et al., 1994;Hall, 1998;Gallo and Letourneau, 2000). The Rho family of GTPases is known to play a major role in this process (for reviews, see Luo et al., 1997;Tapon and Hall, 1997; Aspenstrom, 1999;Mueller, 1999;Song and Poo, 1999;Bishop and Hall, 2000).Members of the family (Cdc42, Rho, and Rac) are either found in the GTP-bound active state or the GDP-bound inactive state (for reviews, see Van Aelst and D'Souza-Schorey, 1997;Mackay and Hall, 1998;Hall 1999;Kjoller and Hall 1999;Bishop and Hall, 2000). Relative abundance of active Rho and Rac might regulate growth cone behavior during axon navigation (Mueller, 1999). Dominant negative and constitutively active versions of Rho GTPases have been used to study their role in axonal arborization (Threadgill et al., 1997;Nakayama et al., 2000), dendritic growth (Threadgill et al., 1997; Ruchoeft et al., 1999;Nakayama et al., 2000;Li et al., 2000), neuronal remodeling (Luo e...

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Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines

Cited by 437 publications

References 26 publications

Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1

Mechanism of activation of Pak1 kinase by membrane localization

Regulation of neurotrophin‐induced axonal responses via Rho GTPases

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