GRAF1 promotes ferlin-dependent myoblast fusion

Kaitlin C. Lenhart, Abby L. Becherer, Jianbin Li, Xiao Xiao, Elizabeth M. McNally, Christopher P. Mack, Joan M. Taylor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Myoblast fusion (a critical process by which muscles grow) occurs in a multi-step fashion that requires actin and membrane remodeling; but important questions remain regarding the spatial/temporal regulation of and interrelationship between these processes. We recently reported that the Rho-GAP, GRAF1, was particularly abundant in muscles undergoing fusion to form multinucleated fibers and that enforced expression of GRAF1 in cultured myoblasts induced robust fusion by a process that required GAP-dependent actin remodeling and BAR domain-dependent membrane sculpting. Herein we developed a novel line of GRAF1-deficient mice to explore a role for this protein in the formation/maturation of myotubes in vivo. Post-natal muscles from GRAF1-depleted mice exhibited a significant and persistent reduction in cross-sectional area, impaired regenerative capacity and a significant decrease in force production indicative of lack of efficient myoblast fusion. A significant fusion defect was recapitulated in isolated myoblasts depleted of GRAF1 or its closely related family member GRAF2. Mechanistically, we show that GRAF1 and 2 facilitate myoblast fusion, at least in part, by promoting vesicle-mediated translocation of fusogenic ferlin proteins to the plasma membrane.

Original languageEnglish (US)
Pages (from-to)298-311
Number of pages14
JournalDevelopmental Biology
Volume393
Issue number2
DOIs
StatePublished - 2014

Keywords

  • Endocytic recycling
  • Ferlin
  • GRAF
  • Myoblast fusion

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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