Netrins and neogenin promote myotube formation.
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.
Kang
Jong-Sun
JS
Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Yi
Min-Jeong
MJ
Zhang
Wei
W
Feinleib
Jessica L
JL
Cole
Francesca
F
Krauss
Robert S
RS
D019898:Autocrine Communication; D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology*; D032446:Myoblasts / Q000378:metabolism; D050778:NFATC Transcription Factors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000502:physiology*; D000075385:Netrins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075385:Netrins; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C107286:CDON protein, human; C091279:neogenin; C119569:netrin-3; C088894:netrin-2