The Arf-GEF Schizo/Loner regulates N-cadherin to induce fusion competence of Drosophila myoblasts

Abstract

Myoblast fusion is a key process in multinucleated muscle formation. Prior to fusion, myoblasts recognize and adhere to each other with the aid of cell-adhesion proteins integrated into the membrane. Their intracellular domains participate in signal transduction by binding to cytoplasmic proteins. Here we identified the calcium-dependent cell-adhesion protein N-cadherin as the binding partner of the guanine-nucleotide exchange factor Schizo/Loner in Drosophila melanogaster. N-cadherin was expressed in founder cells and fusion-competent myoblasts of Drosophila during the first fusion phase. Our genetic analyses demonstrated that the myoblast fusion defect of schizo/loner mutants is rescued in part by the loss-of-function mutation of N-cadherin, which suggests that Schizo/Loner is a negative regulator of N-cadherin. Based on our findings, we propose a model where N-cadherin must be removed from the myoblast membrane to induce a protein-free zone at the cell-cell contact point to permit fusion.

The BRAG/IQSec family of Arf GEFs

“…Interestingly, myoblast fusion defects in loner mutant flies could be partially rescued by a loss of function mutation in N-cadherin, suggesting that surface expression of N-cadherin inhibits fusion, and that Loner may promote fusion by driving N-cadherin endocytosis. 10 In this regard, BRAG2 has been reported to drive endocytosis of another cadherin, E-cadherin, in vertebrate cells in response to both EGF 7 and HGF. 11 It should be noted that while loner was originally characterized as an Arf6 GEF, complete loss of Arf6 in flies does not inhibit myoblast fusion; 12 it is therefore possible that one or more other Arfs fulfill that role.…”

Cadherin switching during the formation and differentiation of the Drosophila mesoderm – implications for epithelial-to-mesenchymal transitions

“…Although the consequences of the loss of function of E-cadherin and N-cadherin in Drosophila have been described previously (Dottermusch-Heidel et al, 2012;Iwai et al, 1997;Oda et al, 1993;Prakash et al, 2005;Tepass and Hartenstein, 1994), the precise roles of these proteins in the earliest stages of mesoderm morphogenesis have not been studied in detail. We therefore reanalysed mutant embryos during gastrulation for subtle morphological defects.…”

Tethering Membrane Fusion: Common and Different Players in Myoblasts and at the Synapse

“…1Ruiz-Gómez et al (2000), Strünkelnberg et al (2001).2Komori et al (2008).3Strünkelnberg et al (2001).4Sugie et al (2010).5Bour et al (2000).6Artero et al (2001), Dworak et al (2001).7Shen and Bargmann (2003).8Shen et al (2004).9Dottermusch-Heidel et al (2012).10Prakash et al (2005).11Fannon and Colman (1996), Uchida et al (1996).12Bao et al (2007).13Najarro et al (2012).14Aravamudan et al (1999).15Maruyama and Brenner (1991).16Brose et al (1995).17Takamori et al (2006).18Estrada et al (2007).19Stevens et al (2012).20Nonet et al (1999).21Stenius et al (1995).22Jahn et al (1985).23Wiedenmann and Franke (1985).24Knaus et al (1990).25Hornbruch-Freitag et al (2011).26Perin et al (1991)27DiAntonio et al (1993).28Nonet et al (1993).…”

“…In contrast to the IgSFs that form a ring-like structure at cell–cell contact points, N-cadherin is uniformly distributed around the plasma membrane of FCs and FCMs (Dottermusch-Heidel et al, 2012). As in mammals, the loss of N-cadherin in Drosophila does not disturb myoblast fusion (Charlton et al, 1997; Dottermusch-Heidel et al, 2012), which points towards compensatory mechanisms. In mammals, N-cadherin is replaced by other members of the classical cadherin family (Krauss, 2010).…”