Genetic Enhancers ofsem-5Define Components of the Gonad-Independent Guidance Mechanism Controlling Sex Myoblast Migration inCaenorhabditis elegansHermaphrodites

Chen, Estella B.; Branda, Catherine; Stern, Michael

doi:10.1006/dbio.1996.8473

Cited by 39 publications

(24 citation statements)

References 37 publications

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“…The combined results of C3 expression and rho-1(RNAi) escapers indicate clearly that rho-1(ϩ) activity is required for P cell migration. unc-73 cause axon guidance defects and failed migrations in some cell types, including P cells (7,(29)(30)(31). We show here that two unc-73 alleles, gm40 and e936, cause similar partial P cell migration defects (Table 1).…”

Section: Methodsmentioning

confidence: 99%

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

Spencer

Orita

Malone

et al. 2001

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

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The Rho family of guanine triphosphate hydrolases controls various cellular processes, including cell migration. We describe here the demonstration of a role for a RhoA GTPase homologue during cell migration in Caenorhabditis elegans. We show that eliminating or reducing rho-1 gene function by using a dominant-negative transgene or dsRNA interference results in a severe defect in migration of hypodermal P cells to a ventral position. Biochemical and genetic data also suggest that unc-73, which encodes a Trio-like guanine nucleotide exchange factor, may act as an activator of rho-1 in the migration process. Mutations in let-502 ROCK, a homologue of a RhoA effector in mammals, also cause defects in P cell migration, suggesting that it may be one of several effectors acting downstream of rho-1 during P cell migration. Finally, we provide evidence to support the idea that other small Rac subfamily small GTPases act redundantly and in parallel to RHO-1 in this specific cell migration event.rho-1 ͉ rac ͉ unc-73

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Section: Methodsmentioning

confidence: 99%

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

Spencer

Orita

Malone

et al. 2001

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

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“…The systematic screen for mutants with severely displaced SMs in a clr-1(e1745ts); sem-5(n1779) sensitized background has been described elsewhere (5). The mutations obtained from this screen fall into two classes.…”

Section: Sm Migrationmentioning

confidence: 99%

egl-17 encodes an invertebrate fibroblast growth factor family member required specifically for sex myoblast migration in Caenorhabditis elegans

Burdine

Chen

Kwok

et al. 1997

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

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The proper guidance of the Caenorhabditis elegans hermaphrodite sex myoblasts (SMs) requires the genes egl-15 and egl-17. egl-15 has been shown to encode the C. elegans orthologue of the fibroblast growth factor receptor (FGFR). Here we clone egl-17 and show it to be a member of the fibroblast growth factor (FGF) family, one of the first functional invertebrate FGFs known. egl-17 shares homology with other FGF members, conserving the key residues required to form the distinctive tertiary structure common to FGFs. Genetic and molecular evidence demonstrates that the SM migration defect seen in egl-17 mutant animals represents complete loss of egl-17 function. While mutations in egl-17 affect only SM migration, mutations in egl-15 can result in larval arrest, scrawny body morphology, and the ability to suppress mutations in clr-1. We propose that EGL-17 (FGF) acts as a ligand for EGL-15 (FGFR) specifically during SM migration and that another ligand(s) activates EGL-15 for its other functions.Egg laying in Caenorhabditis elegans hermaphrodites requires the proper positioning, attachment, and functioning of a set of 16 vulval and uterine muscles. These muscles, collectively called the sex muscles, arise from a pair of bilaterally symmetrical sex myoblast (SM) cells that are born in the posterior body region of C. elegans larvae at the end of the first larval stage. During the second and the early portions of the third larval stage, the SMs migrate anteriorly approximately 65 m to reach the precise center of the developing gonad, where they divide and give rise to the sex muscles (1). The migrations of the SMs are critical for normal egg laying, as SMs that fail to migrate anteriorly result in mispositioned sex muscles and an egg-laying-defective (Egl) phenotype (2).The migrations of the SMs are controlled by two mechanisms (3). A gonad-independent mechanism, revealed by laser removal of the gonad, allows the SMs to migrate anteriorly to a broad range of final positions that span the central region of the animal. The second mechanism allows for the precise positioning of the SMs flanking the center of the gonad. In this gonad-dependent mechanism, somatic cells in the gonad are postulated to send attractive signals to the SMs, resulting in their precise positioning (3).Mutations in two genes, egl-15 and egl-17, alter the interaction between the SMs and the gonad (2). The SMs, normally attracted to the gonad, are actively repelled by the gonad in egl-15 and egl-17 mutant hermaphrodites, resulting in severely posteriorly displaced SMs. Removal of the gonad in egl-15 and egl-17 mutants allows the SMs to migrate further anteriorly, implicating the gonad in the posterior displacement of the SMs in these mutants. The dramatic effects of these mutations on the interactions between the gonad and the SMs implicates egl-15 and egl-17 in the gonad-dependent attractive mechanism.egl-15 was cloned and shown to encode a C. elegans fibroblast growth factor (FGF) receptor (FGFR), implicating FGFR signaling in the guidance of...

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“…Soc mutations in sem-5, the GRB2 ortholog in C. elegans (10); soc-2/sur-8, encoding a leucine-rich repeat protein that binds to LET-60 RAS (44,46); and let-341/sos-1 (8) implicate the RAS/MAPK cascade in mediating this function of EGL-15 signaling. LET-60 RAS function has been implicated in other processes mediated by EGL-15 (9,11,49). Here we present direct evidence for the involvement of LET-60 RAS and members of the MAPK cascade in the Clr/Soc aspect of EGL-15 signaling.…”

mentioning

confidence: 99%

The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

Schutzman

Borland

Newman

et al. 2001

Molecular and Cellular Biology

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EGL-15 is a fibroblast growth factor receptor in the nematode Caenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated both let-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophila and mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways in Drosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15.Receptor tyrosine kinases (RTKs) play critical roles in translating cues gathered from the extracellular environment into biological responses such as cellular differentiation, proliferation, and migration events. RTKs such as the platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) receptors define a family of single-pass transmembrane proteins with an intracellular tyrosine kinase domain (51). Binding of growth factor to the extracellular portions of these receptors promotes receptor dimerization and activation of the intracellular tyrosine kinase domain (43). Receptor activation leads to receptor autophosphorylation as well as phosphorylation of cytoplasmic signaling proteins. Specific phosphotyrosine sites on the receptor can serve to propagate signaling by recruiting Src homology domain 2 (SH2) and PTB domain-containing signaling proteins directly to the activated receptor (37, 38). For example, many RTKs can signal to the RAS/mitogen-activated protein kinase (MAPK) cascade via direct recruitment of the SH2/SH3 domain-containing adaptor protein GRB2 in complex with SOS, the guanine nucleotide exchange factor for RAS (31). EGF and PDGF RTKs can utilize direct recruitment of the GRB2/ SOS complex to achieve RAS activation. This canonical pathway is well-conserved in Caenorhabditis elegans, Drosophila, and mammalian systems (37).There is compelling evidence that the RAS/MAPK signaling pathway plays an important role in signaling via FGF receptors (FGFRs) as well (32). However, unlike the EGF and PDGF receptors, FGFRs do not appear to recruit GRB2/SOS directly. Instead, mammalian FGFR-1 makes use of the m...

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Genetic Enhancers ofsem-5Define Components of the Gonad-Independent Guidance Mechanism Controlling Sex Myoblast Migration inCaenorhabditis elegansHermaphrodites

Cited by 39 publications

References 37 publications

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

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

egl-17 encodes an invertebrate fibroblast growth factor family member required specifically for sex myoblast migration in Caenorhabditis elegans

The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

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