Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 23, Pages 9274-9279Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904398106
Keywords
myoblast fusion; sticks and stones
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Funding
- NICHD NIH HHS [5P30HD018655, P30 HD018655] Funding Source: Medline
- NIDDK NIH HHS [R01 DK055001, DK 55001] Funding Source: Medline
- NINDS NIH HHS [P50 NS040828, R01NS047727, R01 NS047727, 5P50NS040828] Funding Source: Medline
- PHS HHS [K08HLL04216] Funding Source: Medline
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Skeletal muscle is formed via fusion of myoblasts, a well-studied process in Drosophila. In vertebrates however, this process is less well understood, and whether there is evolutionary conservation with the proteins studied in flies is under investigation. Sticks and stones (Sns), a cell surface protein found on Drosophila myoblasts, has structural homology to nephrin. Nephrin is a protein expressed in kidney that is part of the filtration barrier formed by podocytes. No previous study has established any role for nephrin in skeletal muscle. We show, using two models, zebrafish and mice, that the absence of nephrin results in poorly developed muscles and incompletely fused myotubes, respectively. Although nephrin-knockout (nephrin(KO)) myoblasts exhibit prolonged activation of MAPK/ERK pathway during myogenic differentiation, expression of myogenin does not seem to be altered. Nevertheless, MAPK pathway blockade does not rescue myoblast fusion. Co-cultures of unaffected human fetal myoblasts with nephrinKO myoblasts or myotubes restore the formation of mature myotubes; however, the contribution of nephrinKO myoblasts is minimal. These studies suggest that nephrin plays a role in secondary fusion of myoblasts into nascent myotubes, thus establishing a possible functional conservation with Drosophila Sns.
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