The Notch signaling pathway controls growth, differentiation and patterning in divergent animal phyla; in humans, defective Notch signaling has been implicated in cancer, stroke and neurodegenerative disorders. Despite its developmental and medical significance, little is known about the factors that render cells to become competent for Notch signaling. Here we show that during vulval development in the nematode Caenorhabditis elegans the HOX protein LIN-39 and its EXD/PBX-like cofactor CEH-20 are required for LIN-12/Notch-mediated lateral signaling that specifies the 2° vulval cell fate. Inactivation of either lin-39 or ceh-20 resulted in the misspecification of 2° vulval cells and suppressed the multivulva phenotype of lin-12(n137) gain-of-function mutant animals. Furthermore, both LIN-39 and CEH-20 are required for the expression of basal levels of the genes encoding the LIN-12/Notch receptor and one of its ligands in the vulval precursor cells, LAG-2/Delta/Serrate, rendering them competent for the subsequent lin-12/Notch induction events. Our results suggest that the transcription factors LIN-39 and CEH-20, which function at the bottom of the RTK/Ras and Wnt pathways in vulval induction, serve as major integration sites in coordinating and transmitting signals to the LIN-12/Notch cascade to regulate vulval cell fates.

Studies of sex myoblast (SM) migration in the nematode Caenorhabditis elegans have shown that multiple guidance mechanisms cooperate to ensure the accurate and reproducible targeting of the SMs. Many issues arise in the analysis of SM migration, including the action of multiple guidance mechanisms, redundant sources of guidance information, the multiple uses of molecular components, and whether factors affect cell fate determination events or the guidance mechanisms themselves. These issues are common to many cell migration events and make the analysis of SM migration instructive to our general understanding of how cell migrations are controlled.

The migrations of the sex myoblasts in Caenorhabditis elegans hermaphrodites involve two guidance mechanism: a gonad-dependent attraction that confers precise positioning of the sex myoblasts and a gonad-independent mechanism that is sufficient for coarse positioning in the absence of the gonad (Thomas et al., 1990). Here we show that mutations in unc-53, unc-71, and unc-73 disrupt sex myoblast positioning in the absence of the gonad, while they do not affect positioning in the presence of the gonad. Thus, mutations in these genes appear to compromise the gonad-independent mechanism without affecting motility or the gonad-dependent attraction. Mutations in sem-5 confer dramatic sex myoblast positioning defects in double mutant combinations with unc-53, unc-71, or unc-73 mutations, even in the presence of the gonad. This suggests that sem-5 is required for the gonad-dependent attractive mechanism. Mutations in let-60 ras and let-341 also confer sex myoblast migration defects in an unc-53 background, implicating these genes in gonad-dependent positioning as well.

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.

The migrations of the sex myoblasts inCaenorhabditis eleganshermaphrodites involve two guidance mechanisms: a gonad-dependent attraction that confers precise positioning of the sex myoblasts and a gonad-independent mechanism that is sufficient for coarse positioning in the absence of the gonad (Thomaset al.,1990). Here we show that mutations inunc-53, unc-71,andunc-73disrupt sex myoblast positioning in the absence of the gonad, while they do not affect positioning in the presence of the gonad. Thus, mutations in these genes appear to compromise the gonad-independent mechanism without affecting motility or the gonad-dependent attraction. Mutations insem-5confer dramatic sex myoblast positioning defects in double mutant combinations withunc-53, unc-71,orunc-73mutations, even in the presence of the gonad. This suggests thatsem-5is required for the gonad-dependent attractive mechanism. Mutations inlet-60 rasandlet-341also confer sex myoblast migration defects in anunc-53background, implicating these genes in gonad-dependent positioning as well.