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Vol. 20, Issue 23, 4920-4931, December 1, 2009

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

Gyu-Un Bae^*,,, Youn-Joo Yang^*,,, Guoying Jiang^*, Mingi Hong^*, Hye-Jin Lee, Marc Tessier-Lavigne, Jong-Sun Kang^*,, and Robert S. Krauss^*

*Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029; Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea; and Division of Research, Genentech, Inc., South San Francisco, CA 94080

Submitted June 16, 2009; Revised September 8, 2009; Accepted September 28, 2009
Monitoring Editor: Richard K. Assoian

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.

These authors contributed equally to this work.

Address correspondence to: Robert S. Krauss (robert.krauss{at}mssm.edu) or Jong-Sun Kang (jskang{at}med.skku.ac.kr).

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