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J Biol Chem. July 22, 2011; 286 (29): 25903-21.

Skeletal muscle differentiation and fusion are regulated by the BAR-containing Rho-GTPase-activating protein (Rho-GAP), GRAF1.

Doherty JT , Lenhart KC , Cameron MV , Mack CP , Conlon FL , Taylor JM .

Although RhoA activity is necessary for promoting myogenic mesenchymal stem cell fates, recent studies in cultured cells suggest that down-regulation of RhoA activity in specified myoblasts is required for subsequent differentiation and myotube formation. However, whether this phenomenon occurs in vivo and which Rho modifiers control these later events remain unclear. We found that expression of the Rho-GTPase-activating protein, GRAF1, was transiently up-regulated during myogenesis, and studies in C2C12 cells revealed that GRAF1 is necessary and sufficient for mediating RhoA down-regulation and inducing muscle differentiation. Moreover, forced expression of GRAF1 in pre-differentiated myoblasts drives robust muscle fusion by a process that requires GTPase-activating protein-dependent actin remodeling and BAR-dependent membrane binding or sculpting. Moreover, morpholino-based knockdown studies in Xenopus laevis determined that GRAF1 expression is critical for muscle development. GRAF1-depleted embryos exhibited elevated RhoA activity and defective myofibrillogenesis that resulted in progressive muscle degeneration, defective motility, and embryonic lethality. Our results are the first to identify a GTPase-activating protein that regulates muscle maturation and to highlight the functional importance of BAR domains in myotube formation.

PubMed ID: 21622574
PMC ID: PMC3138304
Article link: J Biol Chem.
Grant support: DE-018825 NIDCR NIH HHS, HL-070953 NHLBI NIH HHS , HL-071054 NHLBI NIH HHS , HL-081844 NHLBI NIH HHS , HL-089641 NHLBI NIH HHS , T32 HD046369-05 NICHD NIH HHS , T32HL69768 NHLBI NIH HHS , R01 DE018825 NIDCR NIH HHS, R01 HL102446 NHLBI NIH HHS , R01 HL081844 NHLBI NIH HHS , R01 HL089641 NHLBI NIH HHS , R01 HL071054 NHLBI NIH HHS , R01 HL070953 NHLBI NIH HHS

Genes referenced: actl6a arhgap26 dag1 drg1 hist1h4d mapk1 myod1 pxn rho rho.2 rhoa tnnt2 tpm1 tsc1

Antibodies referenced: Somite Ab1 Tnnt2 Ab1 Tpm1 Ab1
Morpholinos referenced: arhgap26 MO1 arhgap26 MO2

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Benard, 1999, Pubmed[+]

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