CXCR7 promotes foetal myoblast fusion at muscle fiber tips independently of Myomaker via a ß1integrin-EGFR-dependent mechanism

Abstract Muscle growth must be tightly regulated during development in order to obtain the final muscle shape. Myoblast fusion is a critical step of muscle growth, driving the formation of syncytial myofibers attaching at both ends to tendons. We investigated the role of the CXCR7 chemokine receptor in foetal muscle growth during chicken limb development. We show that CXCR7 displays a regionalized expression at the tips of myofibers close to tendons in foetal limb muscles, which is exclusive to the central location of the fusion gene MYOMAKER ( TMEM8C in chicken) in foetal muscles. CXCR7 promotes myoblast fusion independently of TMEM8C in chicken limb muscles and in foetal myoblast cultures and requires EGF receptor signalling. The CXCR7 ligand, CXCL12, expressed in connective tissue, increases ß1integrin activation at the myotendinous junction and CXCR7 expression at muscle tips, resulting in a fusion promoting effect independent from a direct binding of CXCL12 to CXCR7 receptor. Our results evidence a CXCR7-dependent/TMEM8C-independent fusion mechanism at the myofiber tips that regulates muscle growth at the tendon/muscle interface during foetal myogenesis.