title: Myod and H19-Igf2 locus interactions are required for diaphragm formation in the mouse.
abstract: The myogenic regulatory factor Myod and insulin-like growth factor 2 (Igf2) have been shown to interact in vitro during myogenic differentiation. In order to understand how they interact in vivo, we produced double-mutant mice lacking both the Myod and Igf2 genes. Surprisingly, these mice display neonatal lethality due to severe diaphragm atrophy. Alteration of diaphragm muscle development occurs as early as 15.5 days post-coitum in the double-mutant embryos and leads to a defect in the terminal differentiation of muscle progenitor cells. A negative-feedback loop was detected between Myod and Igf2 in embryonic muscles. Igf2 belongs to the imprinted H19-Igf2 locus. Molecular analyses show binding of Myod on a mesodermal enhancer (CS9) of the H19 gene. Chromatin conformation capture experiments reveal direct interaction of CS9 with the H19 promoter, leading to increased H19 expression in the presence of Myod. In turn, the non-coding H19 RNA represses Igf2 expression in trans. In addition, Igf2 also negatively regulates Myod expression, possibly by reducing the expression of the Srf transcription factor, a known Myod activator. In conclusion, Igf2 and Myod are tightly co-regulated in skeletal muscles and act in parallel pathways in the diaphragm, where they affect the progression of myogenic differentiation. Igf2 is therefore an essential player in the formation of a functional diaphragm in the absence of Myod.
authors: Genetics and Development Department, Inserm U1016, CNRS UMR 8104, University of Paris Descartes, Institut Cochin, 75014 Paris, France.
authors: Maud
authors: M
authors: Borensztein
authors: Paul
authors: P
authors: Monnier
authors: Franck
authors: F
authors: Court
authors: Yann
authors: Y
authors: Louault
authors: Marie-Anne
authors: MA
authors: Ripoche
authors: Laurent
authors: L
authors: Tiret
authors: Zizhen
authors: Z
authors: Yao
authors: Stephen J
authors: SJ
authors: Tapscott
authors: Thierry
authors: T
authors: Forné
authors: Didier
authors: D
authors: Montarras
authors: Luisa
authors: L
authors: Dandolo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003964:Diaphragm / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D004622:Embryo, Mammalian; D004843:Epistasis, Genetic / Q000502:physiology*; D005260:Female; D056426:Genetic Loci; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D024510:Muscle Development / Q000235:genetics; D017570:MyoD Protein / Q000235:genetics* / Q000502:physiology; D038081:Organogenesis / Q000235:genetics; D011247:Pregnancy; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000502:physiology
chemical_list: C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II