Netrins and neogenin promote myotube formation

Abstract

Differentiation of skeletal myoblasts into multinucleated myotubes is a multistep process orchestrated by several families of transcription factors, including myogenic bHLH and NFAT proteins. The activities of these factors and formation of myotubes are regulated by signal transduction pathways, but few extracellular factors that might initiate such signals have been identified. One exception is a cell surface complex containing promyogenic Ig superfamily members (CDO and BOC) and cadherins. Netrins and their receptors are established regulators of axon guidance, but little is known of their function outside the nervous system. We report here that myoblasts express the secreted factor netrin-3 and its receptor, neogenin. These proteins stimulate myotube formation and enhance myogenic bHLH- and NFAT-dependent transcription. Furthermore, neogenin binds to CDO in a cis fashion, and myoblasts lacking CDO are defective in responding to recombinant netrin. It is proposed that netrin-3 and neogenin may promote myogenic differentiation by an autocrine mechanism as components of a higher order complex of several promyogenic cell surface proteins.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…It should be noted that the question of neogenin's ligand remains tricky: despite its higher affinity for RGM, neogenin seems to be able to mediate netrin-1 signaling in axon attraction (Wilson and Key, 2006) or cell adhesion (Srinivasan et al, 2003). Moreover, neogenin has also been proposed to mediate netrin-3 signaling during myotube formation (Kang et al, 2004), as well as netrin-4 signaling in angiogenesis (Lejmi et al, 2008).…”

Molecular basis of the myogenic profile of aged human skeletal muscle satellite cells during differentiation

“…Netrins comprise a small family of secreted proteins related to laminins that associate with cell membranes and ECM and are very important to promote myotube formation (Kang et al, 2004). 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 15 Sarcopenic muscle presents atrophy, which depends, at least in part, on a decrease or imbalance in protein metabolism.…”

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

“…Specific netrin and RGM family members function as ligands for neogenin (Cole et al, 2007;Wilson and Key, 2007). Netrin-1 and netrin-3 are expressed in developing mouse skeletal muscle, and cultured murine myoblasts express netrin-3 but little or no netrin-1 (Wang et al, 1999;Kang et al, 2004). We have shown previously that recombinant chicken netrin-2 promotes myotube formation by C2C12 myoblasts in a neogenindependent manner (note that mouse netrin-3 is related to chicken netrin-2 and that there is no netrin-3 in chicken and no netrin-2 in mice; netrin-2, unlike netrin-3, can be obtained in soluble form and is therefore used in our studies; Kang et al, 2004).…”

“…Netrin-1 and netrin-3 are expressed in developing mouse skeletal muscle, and cultured murine myoblasts express netrin-3 but little or no netrin-1 (Wang et al, 1999;Kang et al, 2004). We have shown previously that recombinant chicken netrin-2 promotes myotube formation by C2C12 myoblasts in a neogenindependent manner (note that mouse netrin-3 is related to chicken netrin-2 and that there is no netrin-3 in chicken and no netrin-2 in mice; netrin-2, unlike netrin-3, can be obtained in soluble form and is therefore used in our studies; Kang et al, 2004). RGMc, but not RGMa or RGMb, is expressed in developing muscle and is induced during myoblast differentiation in vitro (Kuninger et al, 2004(Kuninger et al, , 2006Niederkofler et al, 2004;Oldekamp et al, 2004).…”