Semaphorins, commonly known as repulsive axonal guidance cues in vertebrates and insects, regulate epidermal morphogenesis in Caenorhabditis elegans . Plexins, constituting a family of transmembrane proteins, function as receptors for semaphorins and transduce their signals downstream, though little has been understood about the semaphorin-plexin signaling events. In C. elegans , loss-of-function semaphorin (
smp-1 ,
smp-2 ) and plexin (
plx-1 ) mutants exhibit anterior displacement of ray 1 in the male tail, which is presumably the consequence of an aberrant arrangement of the epidermal ray precursors. To gain insight into the semaphorin-plexin signaling, we performed a genetic screen for mutations that suppress the ray 1 phenotype of
plx-1 mutants. A mutation induced by EMS,
nc40 , strikingly suppressed the phenotype of
plx-1 , as well as that of
smp-1 and
smp-2 . SNP mapping, a rescuing experiment, RNAi and a sequence analysis confirmed that
nc40 was a loss-of-function allele of a GCN1 homolog gene (
gcn-1 ). GCN1, which is highly conserved among eukaryotes, functions as a negative regulator for eukaryotic translation initiation factor 2 alpha (eIF2alpha) by participating in its phosphorylation. A loss-of-function mutation in PEK/PERK (
pek-1 ), which would normally phosphorylate and inactivate eIF2alpha independently of GCN1 cascade, also suppressed the phenotype of
plx-1 ,
smp-1 and
smp-2 mutants. Western blot analysis revealed that the level of eIF2alpha phosphorylation was reduced in
gcn-1 and
pek-1 mutants, indicating that
gcn-1 and
pek-1 mutations increase the activity of eIF2alpha and thus the translation initiation is up-regulated. In addition, inactivation of eIF2alpha by RNAi caused ray 1 anterior displacement, the same defect as can be seen in
plx-1 ,
smp-1 and
smp-2 mutants. These results are consistent with the model that the semaphorin-plexin signaling stimulates the translation initiation. Possible mechanism of how translation initiation would regulate epidermal morphogenesis will also be discussed.