A RHO GTPase-mediated pathway is required during P cell migration in
            <i>Caenorhabditis elegans</i>

Spencer, Andrew; Orita, Satoshi; Malone, Christian J.; Han, Min

doi:10.1073/pnas.241504098

Cited by 65 publications

(80 citation statements)

References 45 publications

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“…Therefore, to determine whether OSG-1 can interact with Rho GTPases, as predicted by sequence analysis, we individually knocked down these genes by bacterial RNAi. The ability to turn ON/OFF RNAi at any desired age by feeding C. elegans with RNAi-producing bacteria was a crucial asset to these experiments, because eliminating GTPase activities too early disrupts embryogenesis (Spencer et al 2001). Indeed, RHO-1 or CED42 RNAi treatment from day 0 was lethal (data not shown).…”

Section: Osg-1 Activates a Rho-1 Gtpase Signaling Networkmentioning

confidence: 99%

Guanine Nucleotide Exchange Factor OSG-1 Confers Functional Aging via Dysregulated Rho Signaling in Caenorhabditis elegans Neurons

Duan¹,

Sesti

2014

Genetics

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Rho signaling regulates a variety of biological processes, but whether it is implicated in aging remains an open question. Here we show that a guanine nucleotide exchange factor of the Dbl family, OSG-1, confers functional aging by dysregulating Rho GTPases activities in C. elegans. Thus, gene reporter analysis revealed widespread OSG-1 expression in muscle and neurons. Loss of OSG-1 gene function was not associated with developmental defects. In contrast, suppression of OSG-1 lessened loss of function (chemotaxis) in ASE sensory neurons subjected to conditions of oxidative stress generated during natural aging, by oxidative challenges, or by genetic mutations. RNAi analysis showed that OSG-1 was specific toward activation of RHO-1 GTPase signaling. RNAi further implicated actin-binding proteins ARX-3 and ARX-5, thus the actin cytoskeleton, as one of the targets of OSG-1/RHO-1 signaling. Taken together these data suggest that OSG-1 is recruited under conditions of oxidative stress, a hallmark of aging, and contributes to promote loss of neuronal function by affecting the actin cytoskeleton via altered RHO-1 activity.

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Section: Osg-1 Activates a Rho-1 Gtpase Signaling Networkmentioning

confidence: 99%

Guanine Nucleotide Exchange Factor OSG-1 Confers Functional Aging via Dysregulated Rho Signaling in Caenorhabditis elegans Neurons

Duan¹,

Sesti

2014

Genetics

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“…migration, were previously shown to lead to 60% of L2 larvae with lateral P-cell derivatives (Spencer et al 2001). In our observations of GABA neurons in L2 larvae, we very rarely (eight neurons in 149 L2 toca-1 unc-84 double-mutant animals) observed misplaced neurons at the lateral sides, suggesting we are not studying a general defect in cell migration and can genetically separate nuclear migration from cell migration.…”

Section: Discussionmentioning

confidence: 41%

“…Next, 3.4 kb of the promoter for hlh-3, which is expressed specifically in embryonic and larval P cells, was obtained from pRD1 (Doonan et al 2008) and cloned into the SmaI site of pSL614 to make p hlh-3 ::toca-1::gfp (pSL626). Alternatively, 1.2 kb of the promoter for col-10, which is expressed in embryonic and larval hypodermal cells, was obtained from pOS12 (Spencer et al 2001) and cloned into the SphI and SmaI sites of pSL614 to make p col-10 ::toca-1::gfp (pSL627). p hlh-3 ::toca-1::gfp (2 ng/ml) or p col-10 ::toca-1::gfp (5 ng/ml) was microinjected with odr-1::gfp (100 ng/ml) as a marker into the gonads of young adult hermaphrodites (Mello and Fire 1995).…”

Section: Rna Interference Testsmentioning

confidence: 99%

“…Second, we tested whether wild-type toca-1 could rescue the nuclear migration defect of the yc20 mutation. Wild-type toca-1 was expressed in P cells prior to nuclear migration from two independent promoters: the pan-hypodermal promoter of col-10 ( Spencer et al 2001) and the P-cell-specific promoter of hlh-3 (Doonan et al 2008). The yc20 unc-84(n369) nuclear migration defect was rescued in transgenic animals expressing either p col-10 ::toca-1::gfp or p hlh-3 ::toca-1::gfp.…”

Section: Disruption Of Toca-1 Enhances the Unc-84 Nuclear Migration Dmentioning

confidence: 99%

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toca-1 Is in a Novel Pathway That Functions in Parallel with a SUN-KASH Nuclear Envelope Bridge to Move Nuclei in Caenorhabditis elegans

et al. 2013

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Moving the nucleus to an intracellular location is critical to many fundamental cell and developmental processes, including cell migration, differentiation, fertilization, and establishment of cellular polarity. Bridges of SUN and KASH proteins span the nuclear envelope and mediate many nuclear positioning events, but other pathways function independently through poorly characterized mechanisms. To identify and characterize novel mechanisms of nuclear migration, we conducted a nonbiased forward genetic screen for mutations that enhanced the nuclear migration defect of unc-84, which encodes a SUN protein. In Caenorhabditis elegans larvae, failure of hypodermal P-cell nuclear migration results in uncoordinated and egg-laying-defective animals. The process of P-cell nuclear migration in unc-84 null animals is temperature sensitive; at 25°migration fails in unc-84 mutants, but at 15°the migration occurs normally. We hypothesized that an additional pathway functions in parallel to the unc-84 pathway to move P-cell nuclei at 15°. In support of our hypothesis, forward genetic screens isolated eight emu (enhancer of the nuclear migration defect of unc-84) mutations that disrupt nuclear migration only in a null unc-84 background. The yc20 mutant was determined to carry a mutation in the toca-1 gene. TOCA-1 functions to move P-cell nuclei in a cell-autonomous manner. TOCA-1 is conserved in humans, where it functions to nucleate and organize actin during endocytosis. Therefore, we have uncovered a player in a previously unknown, likely actindependent, pathway that functions to move nuclei in parallel to SUN-KASH bridges. The other emu mutations potentially represent other components of this novel pathway.

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“…In particular, we do not observe embryonic-lethality or cell-migration defects indicative of defects in rho-1 signaling (46,47). It is possible that alternative roles for cnk-1 may be detectable only in the right genetically sensitized background.…”

Section: Discussionmentioning

confidence: 54%

Caenorhabditis elegans CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling

Rocheleau

Rönnlund²,

Tuck³

et al. 2005

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

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Connector enhancer of Ksr (CNK) is a conserved multidomain protein essential for Ras signaling in Drosophila melanogaster and thought to be involved in Raf kinase activation. However, the precise role of CNK in Ras signaling is not known, and mammalian CNKs are proposed to have distinct functions. Caenorhabditis elegans has a single CNK homologue, cnk-1. Here, we describe the role of cnk-1 in C. elegans Ras signaling and its requirements for LIN-45 Raf activation. We find that cnk-1 positively regulates multiple Ras signaling events during development, but, unlike Drosophila CNK, cnk-1 does not appear to be essential for signaling. cnk-1 mutants appear to be normal but show cell-type-specific genetic interactions with mutations in two other Ras pathway scaffolds͞adaptors ksr-1 and sur-8. Genetic epistasis using various activated LIN-45 Raf transgenes shows that CNK-1 promotes LIN-45 Raf activation at a step between the dephosphorylation of inhibitory sites in the regulatory domain and activating phosphorylation in the kinase domain. Our data are consistent with a model in which CNK promotes Raf phosphorylation͞activation through membrane localization, oligomerization, or association with an activating kinase.scaffold ͉ vulva ͉ lin-45

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A RHO GTPase-mediated pathway is required during P cell migration in Caenorhabditis elegans

Cited by 65 publications

References 45 publications

Guanine Nucleotide Exchange Factor OSG-1 Confers Functional Aging via Dysregulated Rho Signaling in Caenorhabditis elegans Neurons

Guanine Nucleotide Exchange Factor OSG-1 Confers Functional Aging via Dysregulated Rho Signaling in Caenorhabditis elegans Neurons

toca-1 Is in a Novel Pathway That Functions in Parallel with a SUN-KASH Nuclear Envelope Bridge to Move Nuclei in Caenorhabditis elegans

Caenorhabditis elegans CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling

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