Vasopressin-dependent myogenic cell differentiation is mediated by both Ca2+/calmodulin-dependent kinase and calcineurin pathways.
Arg8-vasopressin (AVP) promotes the differentiation of myogenic cell lines and mouse primary satellite cells by mechanisms involving the transcriptional activation of myogenic bHLH regulatory factors and myocyte enhancer factor 2 (MEF2). We here report that AVP treatment of L6 cells results in the activation of calcineurin-dependent differentiation, increased expression of MEF2 and GATA2, and nuclear translocation of the calcineurin target NFATc1. Interaction of these three factors occurs at MEF2 sites of muscle specific genes. The different kinetics of AVP-dependent expression of early (myogenin) and late (MCK) muscle-specific genes correlate with different acetylation levels of histones at their MEF2 sites. The cooperative role of calcineurin and Ca2+/calmodulin-dependent kinase (CaMK) in AVP-dependent differentiation is demonstrated by the effect of inhibitors of the two pathways. We show here, for the first time, that AVP, a "novel" myogenesis promoting factor, activates both the calcineurin and the CaMK pathways, whose combined activation leads to the formation of multifactor complexes and is required for the full expression of the differentiated phenotype. Although MEF2-NFATc1 complexes appear to regulate the expression of an early muscle-specific gene product (myogenin), the activation of late muscle-specific gene expression (MCK) involves the formation of complexes including GATA2.
Scicchitano
Bianca Maria
BM
Department of Histology and Medical Embryology, University of Rome La Sapienza, 00161 Roma, Italy.
Spath
Lucia
L
Musarò
Antonio
A
Molinaro
Mario
M
Rosenthal
Nadia
N
Nervi
Clara
C
Adamo
Sergio
S
D000107:Acetylation; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D050989:GATA2 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D002843:Chromatin; D050989:GATA2 Transcription Factor; C494713:Gata2 protein, rat; D006657:Histones; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D001127:Arginine Vasopressin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019703:Calcineurin