G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates
G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates
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DOI：
10.1073/pnas.1313886111
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发表时间：
2014-03-11
影响因子：
11.1
通讯作者：
Cote, Jean-Francois
中科院分区：
文献类型：
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作者：
Hamoud, Noumeira;Tran, Viviane;Cote, Jean-Francois
肌纤维的形成是成肌细胞融合的结果，但在脊椎动物中调节这一过程的细胞表面受体尚不清楚。在果蝇中，成肌细胞融合涉及到由鸟嘌呤核苷酸交换因子myoblast City及其支架蛋白ELMO（细胞表面细胞粘附受体的下游）激活Rac通路。我们之前的研究表明，成肌细胞城的哺乳动物同源物DOCK1以进化保守的方式促进小鼠成肌细胞融合。为了寻找成肌细胞融合的调节因子，我们确定了g蛋白偶联受体脑特异性血管生成抑制剂（BAI3）作为与ELMO相互作用的细胞表面蛋白。在培养细胞中，BAI3或ELMO1/2功能丧失严重损害成肌细胞融合，但不影响分化，不能通过重新表达缺乏ELMO结合的BAI3突变体来挽救。相关BAI蛋白家族成员BAI1在功能上与BAI3不同，因为它不能挽救因BAI3功能丧失而导致的成肌细胞融合缺陷。最后，不能结合ELMO的BAI3突变体的胚胎肌前体表达足以在体内阻断成肌细胞融合。总的来说，我们的发现提供了BAI3在细胞外融合信号传递到细胞内效应物中的作用，确定了它是胚胎脊椎动物成肌细胞融合的重要跨膜蛋白。
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 cell-surface 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.