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XB-ART-43295
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 .


Abstract
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: [+]

Species referenced: Xenopus
Genes referenced: actl6a arhgap26 dag1 drg1 h4c4 mapk1 myod1 pxn rho rho.2 rhoa tnnt2 tpm1 tsc1
Antibodies: Somite Ab1 Tnnt2 Ab1 Tpm1 Ab1
Morpholinos: arhgap26 MO1 arhgap26 MO2


Article Images: [+] show captions
References [+] :
Benard, Characterization of rac and cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. 1999, Pubmed