Semaphorin controls epidermal morphogenesis by stimulating mRNA translation via eIF2α in Caenorhabditis elegans

Abstract

Conserved semaphorin-plexin signaling systems govern various aspects of animal development, including axonal guidance in vertebrates and epidermal morphogenesis in Caenorhabditis elegans. Here we provide in vivo evidence that stimulation of mRNA translation via eukaryotic initiation factor 2␣ (eIF2␣) is an essential downstream event of semaphorin signaling in C. elegans. In semaphorin/plexin mutants, a marked elevation in the phosphorylation of eIF2␣ is observed, which causes translation repression and is causally related to the morphological epidermal phenotype in the mutants. Conversely, removal of constraints on translation by genetically reducing the eIF2␣ phosphorylation largely bypasses requirement for the semaphorin signal in epidermal morphogenesis. We also identify an actin-depolymerizing factor/cofilin, whose expression in the mutants is predominantly repressed, as a major translational target of semaphorin signaling. Thus, our results reveal a physiological significance for translation of mRNAs for cytoskeletal regulators, linking environmental cues to cytoskeletal rearrangement during cellular morphogenesis in vivo.[Keywords: C. elegans; cofilin; eIF2; epidermal morphogenesis; mRNA translation; semaphorin] Supplemental material is available at http://www.genesdev.org.

Functional diversity and mechanisms of action of the semaphorins

“…He expressed Flag-eIF2α specifically in rays and analysed phosphorylation levels following the retrieval of the Flag-tagged proteins. His results show that plexin 1/Smp-1/Smp-2 mutants have substantially elevated levels of phosphorylated eIF2α in their rays compared with wild-type worms (Nukazuka et al, 2008). As the knockdown of ADF/cofilin phenocopies plexin 1/Smp-1/Smp-2 mutants, it appears that the actin-severing protein may be a key target of semaphorin-induced translation, as in the research presented by Holt.…”

Protein Misfolding Induces Hypoxic Preconditioning via a Subset of the Unfolded Protein Response Machinery

“…ok551 has a 1,900-bp deletion (49); tm1153 has a 643-bp frameshift deletion (Wormbase.org). (E) gcn-2(ok871) has a 1,481-bp in-frame deletion starting and ending in exons (33); gcn-2(ok886) has a 1,179-bp in-frame deletion that starts and ends in exons (33). (F) xbp-1(zc12) has an early stop (8).…”

Semaphorin signaling in morphogenesis: found in translation: Figure 1.

“…Perplexingly, deletion of the putative MAB-20 receptor, the divergent B-type plexin PLX-2, has only mild effects on development; MAB-20 signal reception appears to be complex and may involve cell-typedependent cross-talk with L1CAM (Wang et al 2008) and the ephrin EFN-4 (Ikegami et al 2004;Nakao et al 2007). Nukazuka et al (2008) focus on perhaps the best-studied role of SMP/PLX-1 signaling, in positioning of the ray 1 sensillum in the male tail (schematically depicted in Fig. 1B).…”

“…In this issue of Genes & Development, Nukazuka et al (2008) extend our understanding of the mechanism of semaphorin signaling in morphogenetic cell movements. Using a combination of genetic and biochemical analysis, they show that semaphorins stimulate translation in vivo to control an epidermal cell movement in Caenorhabditis elegans.…”