G-protein coupled receptor 56 promotes myoblast fusion through serum response factor- and nuclear factor of activated T-cell-mediated signalling but is not essential for muscle development in vivo. FEBS J 2013 Dec;280(23):6097-113
Date
10/10/2013Pubmed ID
24102982Pubmed Central ID
PMC3877849DOI
10.1111/febs.12529Scopus ID
2-s2.0-84888297031 (requires institutional sign-in at Scopus site) 39 CitationsAbstract
Mammalian muscle cell differentiation is a complex process of multiple steps for which many of the factors involved have not yet been defined. In a screen to identify the regulators of myogenic cell fusion, we found that the gene for G-protein coupled receptor 56 (GPR56) was transiently up-regulated during the early fusion of human myoblasts. Human mutations in the gene for GPR56 cause the disease bilateral frontoparietal polymicrogyria; however, the consequences of receptor dysfunction on muscle development have not been explored. Using knockout mice, we defined the role of GPR56 in skeletal muscle. GPR56(-/-) myoblasts have decreased fusion and smaller myotube sizes in culture. In addition, a loss of GPR56 expression in muscle cells results in decreases or delays in the expression of myogenic differentiation 1, myogenin and nuclear factor of activated T-cell (NFAT)c2. Our data suggest that these abnormalities result from decreased GPR56-mediated serum response element and NFAT signalling. Despite these changes, no overt differences in phenotype were identified in the muscle of GPR56 knockout mice, which presented only a mild but statistically significant elevation of serum creatine kinase compared to wild-type. In agreement with these findings, clinical data from 13 bilateral frontoparietal polymicrogyria patients revealed mild serum creatine kinase increase in only two patients. In summary, targeted disruption of GPR56 in mice results in myoblast abnormalities. The absence of a severe muscle phenotype in GPR56 knockout mice and human patients suggests that other factors may compensate for the lack of this G-protein coupled receptor during muscle development and that the motor delay observed in these patients is likely not a result of primary muscle abnormalities.
Author List
Wu MP, Doyle JR, Barry B, Beauvais A, Rozkalne A, Piao X, Lawlor MW, Kopin AS, Walsh CA, Gussoni EAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlotting, Western
Cell Communication
Cell Differentiation
Cell Fusion
Cell Proliferation
Cells, Cultured
Humans
Immunoenzyme Techniques
Luciferases
Male
Malformations of Cortical Development
Mice
Mice, Knockout
Muscle Development
MyoD Protein
Myoblasts
Myogenin
NFATC Transcription Factors
RNA, Messenger
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Receptors, G-Protein-Coupled
Reverse Transcriptase Polymerase Chain Reaction
Serum Response Element
Signal Transduction
