G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates

Abstract

Muscle fibers form as a result of myoblast fusion, yet the cell surface receptors regulating this process are unknown in vertebrates. In Drosophila, myoblast fusion involves the activation of the Rac pathway by the guanine nucleotide exchange factor Myoblast City and its scaffolding protein ELMO, downstream of cellsurface cell-adhesion receptors. We previously showed that the mammalian ortholog of Myoblast City, DOCK1, functions in an evolutionarily conserved manner to promote myoblast fusion in mice. In search for regulators of myoblast fusion, we identified the G-protein coupled receptor brain-specific angiogenesis inhibitor (BAI3) as a cell surface protein that interacts with ELMO. In cultured cells, BAI3 or ELMO1/2 loss of function severely impaired myoblast fusion without affecting differentiation and cannot be rescued by reexpression of BAI3 mutants deficient in ELMO binding. The related BAI protein family member, BAI1, is functionally distinct from BAI3, because it cannot rescue the myoblast fusion defects caused by the loss of BAI3 function. Finally, embryonic muscle precursor expression of a BAI3 mutant unable to bind ELMO was sufficient to block myoblast fusion in vivo. Collectively, our findings provide a role for BAI3 in the relay of extracellular fusion signals to their intracellular effectors, identifying it as an essential transmembrane protein for embryonic vertebrate myoblast fusion. myotube formation | myogenesis | model system | ced-12 | RhoGTP

Axl Phosphorylates Elmo Scaffold Proteins To Promote Rac Activation and Cell Invasion

“…We reexpressed Elmo1, since the exogenous MycElmo2 was difficult to express in Elmo2 siRNA-treated cells (the human Elmo2 SmartPool siRNA also targets murine mRNA). We also previously reported that biological functions of Elmo1 and Elmo2 in myoblast fusion are interchangeable (54). We observed that expression of Myc-Elmo1 in Elmo2 knockdown cells completely restored the invasion to an extent comparable to that for cells expressing a control siRNA (Fig.…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…Two laboratories recently made exciting discoveries regarding the functions of ADGRB1 (BAI1) and ADGRB3 (BAI3) in this system (Hochreiter-Hufford et al, 2013;Hamoud et al, 2014). Both proteins were reported to be expressed by myoblasts and to promote myoblast fusion into muscle fibers in vitro, but there appear to be differences regarding the in vivo context in which each protein functions, and these differences will be an interesting area for future study.…”

“…Indeed, the ICD of ADGRB1 (BAI1) forms a complex with ELMO (engulfment and cell motility) and Dock180 (dedicator of cytokinesis) and mediates phagocytosis of apoptotic cells and Gram-negative bacteria as well as myoblast fusion via an ELMO/Dock180/Rac signaling module (Park et al, 2007;Das et al, 2011Das et al, , 2014Hochreiter-Hufford et al, 2013). Similarly, BAI3 promotes myoblast fusion through ELMO/DOCK1 (Hamoud et al, 2014). A recent study showed that ADGRB1 (BAI1) also interacts with Par3/Tiam1 and recruits these proteins to synaptic sites for spinogenesis and synaptogenesis (Duman et al, 2013).…”

“…ADGRB1 (BAI1), ADGRB3 (BAI3), and ADGRG1 (GPR56) promote myoblast fusion to form mature multinucleated skeletal muscle fibers (Hochreiter-Hufford et al, 2013;Wu et al, 2013;Hamoud et al, 2014). Apoptotic myoblasts expose phosphatidylserine, which activates ADGRB1 (BAI1) signaling on healthy myoblasts to promote fusion with myoblast and myotubes.…”

Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation

“…Through these protein interactions, Elmo proteins are ideal candidates to coordinate the activation of downstream effectors at the plasma membrane. For instance, the interaction of Elmo1/2 with BAI (brain-specific angiogenesis inhibitor) recruits them onto the proximal membrane to activate the small GTPase Rac1 through the Dock180 guanine nucleotide exchange factor to mediate engulfment of apoptotic cells or to promote muscle differentiation (5,6). In addition, Elmo2 has been implicated in Akt activation, probably through the interaction with small GTPases, such as RhoG (9 -11).…”