title: Cooperative synergy between NFAT and MyoD regulates myogenin expression and myogenesis.
abstract: Calcineurin/NFAT signaling is involved in multiple aspects of skeletal muscle development and disease. The myogenic basic helix-loop-helix transcription factors, MyoD, myogenin, Myf5, and MRF4 specify the myogenic lineage. Here we show that calcineurin/NFAT (nuclear factor of activated T cells) signaling is required for primary myogenesis by transcriptional cooperation with the basic helix-loop-helix transcription factor MyoD. Calcineurin/NFAT signaling is involved in myogenin expression in differentiating myoblasts, where the myogenic regulatory factor MyoD synergistically cooperates with NFATc2/c3 at the myogenin promoter. Using gel shift and chromatin immunoprecipitation assays, we identified two conserved NFAT binding sites in the myogenin promoter that were occupied by NFATc3 upon skeletal muscle differentiation. The transcriptional integration between NFATc3 and MyoD is crucial for primary myogenesis in vivo, as myogenin expression is weak in myod:nfatc3 double null embryos, whereas myogenin expression is unaffected in embryos with null mutations for either factor alone. Thus, the combined findings provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis.
authors.affiliation: The Hubrecht Institute and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, 3584 CT Utrecht, The Netherlands.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Armand
authors.forename: Meriem
authors.initials: M
authors.lastname: Bourajjaj
authors.forename: Sara
authors.initials: S
authors.lastname: Martínez-Martínez
authors.forename: Hamid
authors.initials: H
authors.lastname: el Azzouzi
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.forename: Pantelis
authors.initials: P
authors.lastname: Hatzis
authors.forename: Tim
authors.initials: T
authors.lastname: Seidler
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D017570:MyoD Protein / Q000378:metabolism*; D018008:Myogenin / Q000096:biosynthesis* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; D050778:NFATC Transcription Factors; D019703:Calcineurin