Thinking Globally, Acting Locally

Abstract

Semaphorins function in neuronal pathfinding by stimulating the translation of transcripts localized to the growth cone. Targets of semaphorin-induced translation include cofilin and other proteins that promote depolymerization of F-actin and growth cone collapse. New findings from Nukazuka et al . (see commentary by Chisholm) suggest that semaphorin signaling is also required for the proper positioning of epithelial sensory organs called rays in the male C. elegans tail. In animals that carry loss-of-function mutations in both semaphorin-1 ( smp-1) and smp-2 or in the semaphorin receptor plexin-1 ( plx-1 ), the anteriormost ray is mispositioned, and this phenotype can be rescued by mutation of gcn-1 , which encodes a translational repressor. GCN1 activates GCN2, a kinase that represses eukaryotic translation initiation factor 2α (eIF2α). In a series of genetic interaction and overexpression experiments coupled with Western analysis, the authors demonstrated that phosphorylation of eIF2α (P-eIF2α) increased upon semaphorin signaling and decreased in gcn-1 mutants. They also showed that expression of a constitutively active form of eIF2α phenocopied the defects observed in the plx and smp mutants. Because P-eIF2α is a known translational stimulator, they examined expression and translation of the C. elegans cofilin homolog unc-60 in tail ray development. Semaphorin signaling stimulated unc-60 translation through indirect repression of eIF2α activity. Thus, semaphorin-mediated translational regulation is not limited to cells with highly asymmetric shapes such as neurons. Semaphorin signaling may also play a role in positioning epithelial cells, which, although polarized, are not as irregularly shaped as migrating neurons. A. Nukazuka, H. Fujisawa, T. Inada, Y. Oda, S. Takagi, Semaphorin controls epidermal morphogenesis by stimulating mRNA translation via eIF2α in Caenorhabditis elegans . Genes Dev. 22 , 1025-1036 (2008). [Abstract] [Full Text] A. D. Chisholm, Semaphorin signaling in morphogenesis: Found in translation. Genes Dev. 22 , 955-959 (2008). [Abstract] [Full Text]