Academic journal article Genetics

The Plexin PLX-2 and the Ephrin EFN-4 Have Distinct Roles in MAB-20/semaphorin 2A Signaling in Caenorhabditis Elegans Morphogenesis

Academic journal article Genetics

The Plexin PLX-2 and the Ephrin EFN-4 Have Distinct Roles in MAB-20/semaphorin 2A Signaling in Caenorhabditis Elegans Morphogenesis

Article excerpt

Semaphorins are extracellular proteins that regulate axon guidance and morphogenesis by interacting with a variety of cell surface receptors. Most semaphorins interact with plexin-containing receptor complexes, although some interact with non-plexin receptors. Class 2 semaphorins are secreted molecules that control axon guidance and epidermal morphogenesis in Drosophila and Caenorhabditis elegans. We show that the C. elegans class 2 semaphorin MAB-20 binds the plexin PLX-2. plx-2 mutations enhance the phenotypes of hypomorphic mab-20 alleles but not those of mab-20 null alleles, indicating that plx-2 and mab-20 act in a common pathway. Both mab-20 and plx-2 mutations affect epidermal morphogenesis during embryonic and in postembryonic development. In both contexts, plx-2 null mutant phenotypes are much less severe than mab-20 null phenotypes, indicating that PLX-2 is not essential for MAB-20 signaling. Mutations in the ephrin efn-4 do not synergize with mab-20, indicating that EFN-4 may act in MAB-20 signaling. EFN-4 and PLX-2 are coexpressed in the late embryonic epidermis where they play redundant roles in MAB-20-dependent cell sorting.

SEMAPHORINS are secreted molecules first identi- fied as axon guidance cues causing growth cone collapse (FAN et al. 1993; KOLODKIN et al. 1993). Semaphorins have subsequently been shown to play myriads of roles in neural and non-neural development, including cell migration (KRUGER et al. 2005), tissue morphogenesis (HINCK 2004), formation of the vascular system (SUCHTING et al. 2006), and regulation of the immune system (TAKEGAHARA et al. 2005). The semaphorin family comprises a large number of secreted and transmembrane proteins sharing the signature sema domain of 500 amino acid residues (SEMAPHORIN NOMENCLATURE COMMITTEE 1999). Semaphorins have been classified by domain architecture and by sequences of their sema domains (KOLODKIN et al. 1993). Classes 1 and 2 are invertebrate specific, whereas classes 3, 4, and 7 are found only in vertebrates; class 5 is found in both vertebrates and invertebrates. Class 2 semaphorins are composed of an N-terminal sema domain, a cysteinerich domain, and a C-terminal immunoglobulin domain; interestingly, class 2 semaphorins do not contain motifs mediatingmembrane attachment, yet appear to function as short-range signals. Expression of Drosophila Sema II/Sema-2a on specific muscles causes them to repel axonal growth cones (MATTHES et al. 1995; WINBERG et al. 1998). Sema-2a also acts at short range to repel larval sensory neurons (BATES and WHITINGTON 2007). In contrast, Sema-2a is a long-range chemorepulsive guidance cue in grasshoppers (ISBISTER et al. 1999, 2003). In Caenorhabditis elegans, the class 2 semaphorin MAB-20 promotes separation between epidermal cells (ROY et al. 2000); it is not known whether this reflects a long- or short-range role for MAB-20, which is widely expressed.

Semaphorins interact with a remarkably diverse set of cell surface receptors. One major class of cell surface receptors are the plexins, transmembrane proteins first identified as antigens expressed in restricted regions in the nervous system (OHTA et al. 1992, 1995; KAMEYAMA et al. 1996a,b; FUJISAWA et al. 1997) and as molecules with a Met-related motif (Maestrini et al. 1996). Some transmembrane semaphorins, such as the invertebrate class 1 semaphorins, directly bind plexins (WINBERG et al. 1998). Plexins themselves contain an N-terminal sema domain that binds the sema domain of the semaphorin. Plexins also contain cysteine-rich repeats known as Met-related sequences (MRS) or plexin/semaphorin/ integrin domains and three glycine-proline-rich (GP) repeats; the roles of these domains are not well understood. Class 3 semaphorins interact with receptor complexes composed of plexins and neuropilins (TAMAGNONE et al. 1999). In such receptor complexes, semaphorins bind the neuropilin subunit whereas the plexin is essential for signal transduction into the cell via its cytoplasmic domain. …

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