The Drosophila Trio Plays an Essential Role in Patterning of Axons by Regulating Their Directional Extension

Awasaki, Takeshi; Saito, Mai; Sone, Masaki; Suzuki, Emiko; Sakai, Ryoko; Ito, Kei; Hama, Chihiro

doi:10.1016/s0896-6273(00)81143-5

Cited by 196 publications

(207 citation statements)

References 36 publications

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“…It is suggested that Rho is activated via repulsive axon guidance cues, whereas Rac is activated via attractive cues (Mueller, 1999;Awasaki et al, 2000). Inactivation of Rho initiates neurite outgrowth (Jin and Strittmatter, 1997;Lehmann et al, 1999), and perturbations in Rho activity result in directional changes of growing axons (Awasaki et al, 2000).…”

Section: Rho Activity and Direction Of Axonal Outgrowthmentioning

confidence: 99%

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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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Section: Rho Activity and Direction Of Axonal Outgrowthmentioning

confidence: 99%

“…Recently Trio, a unique GEF that has binding domains for both Rac and Rho, has been studied in detail in Dro-sophila (Awasaki et al, 2000;Bateman et al, 2000;Liebl et al, 2000;Newsome et al, 2000). Trio activates Rac selectively by its GEF1 domain, and the GEF2 domain shows specificity for Rho (Debant et al, 1996).…”

Section: Balance Between Rac and Rhomentioning

confidence: 99%

Regulation of neurotrophin‐induced axonal responses via Rho GTPases

Özdinler

Erzurumlu

2001

J of Comparative Neurology

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“…Among Dbl-GEFs, several GEFs for Rac have been suggested to participate in nervous system development. Still life (SIF) and Trio in Drosophila, Unc-73 in Caenorhabditis elegans, and Kalirins in mammals were shown to take part in synaptogenesis, neuritogenesis, axonal pathfinding, or dendritic morphogenesis (Sone et al, 1997Steven et al, 1998;Awasaki et al, 2000;Lin and Greenberg, 2000;Penzes et al, 2003). Observations from our group and others also suggested that STEF (SIF and Tiam1-like exchange factor) and Tiam1 (Tcell lymphoma invasion and metastasis 1), both orthologs of Drosophila SIF, are involved in neuritogenesis as well as neuronal migration Kunda et al, 2001;Matsuo et al, 2002;Kawauchi et al, 2003;Matsuo et al, 2003;Tanaka et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Involvement of a Rac Activator, P-Rex1, in Neurotrophin-Derived Signaling and Neuronal Migration

Yoshizawa¹,

Kawauchi²,

Sone³

et al. 2005

J. Neurosci.

108

114

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Rho-family GTPases play key roles in regulating cytoskeletal reorganization, contributing to many aspects of nervous system development. Their activities are known to be regulated by guanine nucleotide exchange factors (GEFs), in response to various extracellular cues. P-Rex1, a GEF for Rac, has been mainly investigated in neutrophils, in which this molecule contributes to reactive oxygen species formation. However, its role in the nervous system is essentially unknown. Here we describe the expression profile and a physiological function of P-Rex1 in nervous system development. In situ hybridization revealed that P-Rex1 is dynamically expressed in a variety of cells in the developing mouse brain, including some cortical and DRG neurons. In migrating neurons in the intermediate zone, P-Rex1 protein was found to localize in the leading process and adjacent cytoplasmic region. When transfected in pheochromocytoma PC12 cells, P-Rex1 can be activated by NGF, causing an increase in GTP-bound Rac1 and cell motility. Deletion analyses suggested roles for distinct domains of this molecule. Experiments using a P-Rex1 mutant lacking the Dbl-homology domain, a dominant-negative-like form, and small interfering RNA showed that endogenous P-Rex1 was involved in cell migration of PC12 cells and primary cultured neurons from the embryonic day 14 cerebral cortices, induced by extracellular stimuli (NGF, BDNF, and epidermal growth factor). Furthermore, in utero electroporation of the mutant protein into the embryonic cerebral cortex perturbed radial neuronal migration. These findings suggest that P-Rex1, which is expressed in a variety of cell types, is activated by extracellular cues such as neurotrophins and contributes to neuronal migration in the developing nervous system.

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“…Les mutants unc-73 présen-tent de nombreux défauts de migration des cellules neuronales, mais aussi de guidage et de fasciculation des axones [23]. Plusieurs études indépendantes ont identifié l'orthologue de Trio chez la drosophile [24][25][26][27]. Drosophila Trio (D-Trio) a été en particulier isolé par un crible permettant d'identifier des gènes impliqués dans le guidage axonal des cellules photoréceptrices de l'oeil [24].…”

Section: Trio Contrôle L'activation De Plusieurs Gtpasesunclassified

“…Si le rôle du premier domaine GEF de Trio semble être prépondérant dans le contrôle du guidage axonal par D-Trio, celui du second domaine reste obscur. Cependant, dans les mutants trio chez la drosophile, on observe chez l'adulte une extension anormale des dendrites au niveau d'une structure particulière du cerveau, les corps pédonculés, et ce phé-notype est tout à fait similaire à celui observé dans des mutants de la GTPase RhoA [27]. Ainsi, D-Trio activerait Rac via son premier domaine GEF pour contrôler le guidage axonal, et activerait RhoA via son second domaine pour contrôler la morphologie dendritique.…”

Section: Trio Contrôle L'activation De Plusieurs Gtpasesunclassified