Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Semaphorin signaling in morphogenesis: found in translation Andrew D. Chisholm1 Division of Biological Sciences, Section of Neurobiology, Section of Cell and Developmental Biology, University of California at San Diego, La Jolla, California 92093, USA Semaphorins play diverse roles in axon guidance and ep- local actin and tubulin cytoskeleton, coupled with inhi- ithelial morphogenetic cell movements. In this issue of bition of integrin-mediated adhesion. These cytoskeletal Genes & Development, Nukazuka and colleagues (pp. effects can be mediated by small GTPases, including 1025–1036) show that semaphorins regulate Caenorhab- Rac, Rho, and Ras (Tran et al. 2007). Additionally, it is ditis elegans male tail morphogenesis by stimulating the now clear that axon guidance can involve local transla- translation of specific messages, including the actin-de- tion of cytoskeletal components and regulators within polymerizing enzyme cofilin. the growth cone or axon. Seminal work by the Holt labo- ratory (Campbell and Holt 2001) revealed that local translation was required for growth cones to be repelled Semaphorins form one of the major classes of intercel- by semaphorin 3A in vitro. Not only is translation re- lular signaling pathways in developmental biology. Ini- quired for this response, but Sema3A can directly acti- tially defined by their repellent effects on axonal growth vate TOR kinase-mediated phosphorylation and inhibit cones, semaphorins were found later to also attract the translational initiation repressor eIF4E-BP1. This growth cones (Polleux et al. 2000), and are now recog- likely results in general stimulation of translation by nized as regulators of many nonneuronal developmental activation of eIF4E. Specificity arises from the localiza- processes including morphogenesis of epithelial and en- tion of specific messages to growth cones, so that only dothelial tissues (Hinck 2004; Tran et al. 2007). Accom- axonally localized messages undergo stimulated transla- panying, and possibly explaining, this diversity of bio- tion. logical functions for semaphorins is a strikingly diverse Is translation stimulation used by semaphorins in array of signaling mechanisms. Most semaphorins exert their guises as cell adhesion or tissue remodeling factors? their effects via a conserved family of transmembrane In this issue of Genes & Development, Nukazuka et al. receptors, the plexins. Vertebrate-secreted semaphorins (2008) extend our understanding of the mechanism of do not bind plexins directly, but instead usually bind semaphorin signaling in morphogenetic cell movements. obligate coreceptors called neuropilins, which then acti- Using a combination of genetic and biochemical analy- vate a semaphorin–neuropilin–plexin holoreceptor com- sis, they show that semaphorins stimulate translation in plex. The ability of neuropilins or plexins to couple to vivo to control an epidermal cell movement in Cae- multiple coreceptors may explain the distinct readouts norhabditis elegans. Moreover, they find that semaphor- of semaphorin signaling (Tamagnone and Comoglio 2004): ins stimulate translation in responding cells via the ini- For example, Sema6D can promote or inhibit cell migra- tiation factor eIF2␣, and that a major target of sema- tion in cardiac morphogenesis depending on whether its phorin-stimulated translation is the actin-severing receptor Plexin-A1 couples with two different receptor enzyme ADF/cofilin. tyrosine kinases (Toyofuku et al. 2004). A major goal in analysis of semaphorin signaling is to understand how the different receptor complexes can have distinct (and Semaphorin signaling in C. elegans epidermal sometimes opposing) biological effects. morphogenesis How do semaphorin signaling pathways in morphoge- Semaphorin signaling in C. elegans involves a relatively netic movements compare with the more “canonical” small number of players: three semaphorins, two plex- pathways studied in growth cone repulsion? Semaphorin- ins, and no neuropilins (Fig. 1A). Two related transmem- induced growth cone collapse involves disruption of the brane semaphorins, SMP-1 and SMP-2, have partly re- dundant roles in signaling via the A-type plexin PLX-1 (Fujii et al. 2002; Dalpe et al. 2004). SMP-1 and SMP-2 are [Keywords: C. elegans; cofilin; eIF2; epidermal morphogenesis; mRNA class I semaphorins, and are structurally similar to ver- translation; semaphorin] tebrate class VI. The known functions of the SMP-1/2/ 1Correspondence. E-MAIL [email protected]; FAX (858) 534-7773. PLX-1 pathway are in morphogenesis of epidermal cells Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1669308. and epidermally derived sensilla in sexually dimorphic GENES & DEVELOPMENT 22:955–959 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org 955 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Chisholm Figure 1. (A) Semaphorins and their recep- tors in C. elegans. Two class I semaphorins, SMP-1 and SMP-2, function partly redun- dantly in PLX-1 plexin signaling. The secreted class 2 semaphorin MAB-20 binds PLX-2 (Na- kao et al. 2007); however, genetic data indi- cate PLX-2 must act in concert with other re- ceptors. (B) Positioning of ray cells in the male tail epithelium. Schematic diagram of part of the lateral male tail, anterior to the left and dorsal up. Epidermal cells are in orange, and the ray cell group cells (two neurons and a structural cell) are blue. In the wild type, ray groups 1 and 2 form next to each other in the lateral epidermis; ray 1’s posterior position is dependent on attractive semaphorin signaling from the hook (green). Ray group 1 normally clusters at the junction between R1.p and R2.p (which later fuse). In animals lacking the semaphorin signal, the R1.p cell is smaller; as a consequence, the ray 1 cell group is sepa- rated from ray 2. A more anatomically correct view of ray formation is given at http://www.wormatlas.org. (C) Signaling from PLX-1 activates translation via eIF2␣. PLX-1 reduces the level of phospho-eIF2␣ by an unknown signaling pathway. GCN-1 and PEK-1 together increase phospho-eIF2␣, either indirectly or directly. structures in the male tail and hermaphrodite vulva (Liu ing depending on the genetic background. As ray 1 is et al. 2005). In contrast, loss of function in the secreted normally positioned in ∼20% of plx-1-orsmp-null mu- class 2 semaphorin MAB-20 has more drastic effects on tants, a second pathway is thought to act in parallel to neuronal development and epidermal morphogenesis the SMP/PLX-1 pathway to allow ray 1 to reside in its (Roy et al. 2000). Perplexingly, deletion of the putative normal posterior location. MAB-20 receptor, the divergent B-type plexin PLX-2, has only mild effects on development; MAB-20 signal recep- Genetic screens identify translational controls tion appears to be complex and may involve cell-type- dependent cross-talk with L1CAM (Wang et al. 2008) and To find new components of the SMP/PLX-1 pathway the ephrin EFN-4 (Ikegami et al. 2004; Nakao et al. 2007). Nukazuka et al. (2008) took a classical genetic approach; Nukazuka et al. (2008) focus on perhaps the best-stud- namely, to screen for second site suppressors of the plx-1 ied role of SMP/PLX-1 signaling, in positioning of the ray ray 1 position defect. This screen netted a single allele of 1 sensillum in the male tail (schematically depicted in gcn-1, the C. elegans ortholog of the translational regu- Fig. 1B). The C. elegans male tail is a complex sensory lator GCN1. GCN1’s function in translational control organ essential for male mating and contains nine bilat- was elegantly dissected by genetic and biochemical erally paired sensilla, known as rays, arrayed in stereo- analysis of amino acid starvation responses in yeast typed positions along the anteroposterior axis (Baird et (Hinnebusch 2005). GCN1 regulates translation initia- al. 1991). Each ray sensillum develops from a single neu- tion by repressing the ability of the initiation factor roepithelial precursor (“Rn cell”) that divides to generate eIF2␣ to form the ternary complex with GTP and Met- Met ␣ an epidermal cell, two neurons, and the structural cell tRNAi . GCN1 does not interact with eIF2 directly, of the sensillum. The final position of the sensillum but activates the eIF2␣ kinase GCN2, which itself phos- within the epithelium is thought to be determined pri- phorylates and inactivates eIF2␣. Loss of function in marily by the adhesive contacts of its epidermal cell gcn-1 should globally increase translation, and indeed (Rn.p). Loss of function in plx-1 or in smp-1 smp-2 Nukazuka et al. (2008) show that whole-animal levels of double mutants (hereafter, smp mutants) results in an phospho-eIF2␣ are decreased in their gcn-1 mutants. abnormally shaped R1.p cell, leading to anterior mispo- Somewhat unexpectedly, knockdown of the C. elegans sitioning of ray 1 precursors and an anteriorly displaced GCN2 ortholog did not suppress plx-1, although it did ray 1 sensillum. Previous work suggested that ray 1 pre- reduce whole-animal phospho-eIF2␣ levels; it is not cursors (expressing PLX-1) are somehow attracted to known if the GCN1/GCN2 pathway defined from yeast SMP-expressing cells of a more posterior sensillum, the is precisely conserved in C. elegans. In contrast, muta- hook (Dalpe et al. 2004), although it has remained un- tions in a second eIF2␣ kinase, PEK-1/PERK, partially clear if this involves direct contact between ray 1 cells suppressed plx-1. gcn-1 pek-1 double mutants have very and hook cells, or cleavage and release of the transmem- little phospho-eIF2␣ and strongly (although not com- brane SMPs and their local diffusion. Both the SMP/PLX- pletely) suppress the ray 1 defects of plx-1, suggesting that 1-dependent posterior attraction and SMP/PLX-1-inde- GCN-1 and PEK-1 act in parallel to phosphorylate eIF2␣.