Semaphorins and ephrins are two conserved families of proteins identified as repulsive guidance cues for developing axons. Recent studies have revealed a broader role for semaphorins in neural crest cell migration, heart and bone development and modulation of the immune response. In C. elegans, secreted semaphorin-2a/mab-20 and ephrin
efn-4/mab-26 signaling functions primarily to regulate epidermal morphogenesis during ventral enclosure and sorting of sensory-ray precursor cells during ray morphogenesis (Roy et al., 2000; Chin-Sang et al., 2002; Baird et al., 1991). Although ephrin and semaphorin signaling were previously thought of as independent signaling pathways in axon guidance and development, we present a genetic model demonstrating an integrated ephrin/semaphorin signaling control regulating ventral enclosure and ray precursor cell sorting. Several erf (enhancer of ray fusion) mutations were identified in an enhancer screen for the ray fusion defect of a weak allele of
mab-20. In addition, an allele for C. elegans plexin
plx-2 was also identified consistent with the knowledge that plexins function as specific receptors for semaphorins.
plx-2 expression is able to confer the cell-specific function of ubiquitously expressed
mab-20 in a subset of ray neuroblasts (RnA) during ray precursor cell sorting, pocket cell P neuroectoblasts (P-cells) and ventral substrate neuroblasts for the overlying P-cell migration in pocket enclosure during ventral enclosure. Additional alleles of
plx-2 including a putative null allele have been isolated for genetic analysis. Our genetic analysis shows that; (1)
plx-2 encodes a receptor for
mab-20 signaling to regulate pocket closure and ray morphogenesis. (2)
mab-20 also signals in parallel to
plx-2 through a functionally redundant non-homologous receptor. (3)
mab-26 signals in a common genetic pathway with
mab-20 but in parallel to
plx-2. (4)
erf-1 and
erf-2 signal in the
mab-20 pathway but in parallel to
plx-2 shown by a synthetic ray fusion defect (Syn-Mab). (5)
erf-2 signals in the common genetic pathway of
mab-20 and
mab-26. We also present a cellular model for
mab-20-dependent guidance of pocket cell migration during ventral enclosure and show that the C. elegans Eph receptor
vab-1 functions in a parallel to
plx-2 to sort a
plx-2 neuroblast substrate domain required for the guidance of pocket cell migration.