151. Neogenin regulates skeletal myofiber size and focal adhesion kinase and extracellular signal-regulated kinase activities in vivo and in vitro.
- Author
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Bae GU, Yang YJ, Jiang G, Hong M, Lee HJ, Tessier-Lavigne M, Kang JS, and Krauss RS
- Subjects
- Animals, Cadherins genetics, Cadherins metabolism, Cell Differentiation physiology, Cells, Cultured, Desmin metabolism, Embryo, Mammalian, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases genetics, Focal Adhesion Protein-Tyrosine Kinases genetics, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Morphogenesis, Muscle, Skeletal embryology, Muscle, Skeletal metabolism, Mutation, Myoblasts cytology, Myoblasts metabolism, Myogenin metabolism, Nerve Growth Factors genetics, Nerve Growth Factors metabolism, Netrins, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Focal Adhesion Protein-Tyrosine Kinases metabolism, Membrane Proteins metabolism, Muscle, Skeletal cytology, Signal Transduction physiology
- Abstract
A variety of signaling pathways participate in the development of skeletal muscle, but the extracellular cues that regulate such pathways in myofiber formation are not well understood. Neogenin is a receptor for ligands of the netrin and repulsive guidance molecule (RGM) families involved in axon guidance. We reported previously that neogenin promoted myotube formation by C2C12 myoblasts in vitro and that the related protein Cdo (also Cdon) was a potential neogenin coreceptor in myoblasts. We report here that mice homozygous for a gene-trap mutation in the Neo1 locus (encoding neogenin) develop myotomes normally but have small myofibers at embryonic day 18.5 and at 3 wk of age. Similarly, cultured myoblasts derived from such animals form smaller myotubes with fewer nuclei than myoblasts from control animals. These in vivo and in vitro defects are associated with low levels of the activated forms of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), both known to be involved in myotube formation, and inefficient expression of certain muscle-specific proteins. Recombinant netrin-2 activates FAK and ERK in cultured myoblasts in a neogenin- and Cdo-dependent manner, whereas recombinant RGMc displays lesser ability to activate these kinases. Together, netrin-neogenin signaling is an important extracellular cue in regulation of myogenic differentiation and myofiber size.
- Published
- 2009
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