title: Sim2 prevents entry into the myogenic program by repressing MyoD transcription during limb embryonic myogenesis.
abstract: The basic helix-loop-helix transcription factor MyoD is a central actor that triggers the skeletal myogenic program. Cell-autonomous and non-cell-autonomous regulatory pathways must tightly control MyoD expression to ensure correct initiation of the muscle program at different places in the embryo and at different developmental times. In the present study, we have addressed the involvement of Sim2 (single-minded 2) in limb embryonic myogenesis. Sim2 is a bHLH-PAS transcription factor that inhibits transcription by active repression and displays enhanced expression in ventral limb muscle masses during chick and mouse embryonic myogenesis. We have demonstrated that Sim2 is expressed in muscle progenitors that have not entered the myogenic program, in different experimental conditions. MyoD expression is transiently upregulated in limb muscle masses of Sim2(-/-) mice. Conversely, Sim2 gain-of-function experiments in chick and Xenopus embryos showed that Sim2 represses MyoD expression. In addition, we show that Sim2 represses the activity of the mouse MyoD promoter in primary myoblasts and is recruited to the MyoD core enhancer in embryonic mouse limbs. Sim2 expression is non-autonomously and negatively regulated by the dorsalising factor Lmx1b. We propose that Sim2 represses MyoD transcription in limb muscle masses, through Sim2 recruitment to the MyoD core enhancer, in order to prevent premature entry into the myogenic program. This MyoD repression is predominant in ventral limb regions and is likely to contribute to the differential increase of the global mass of ventral muscles versus dorsal muscles.
authors.affiliation: UPMC, Université Paris 06, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Havis
authors.forename: Pascal
authors.initials: P
authors.lastname: Coumailleau
authors.forename: Aline
authors.initials: A
authors.lastname: Bonnet
authors.forename: Keren
authors.initials: K
authors.lastname: Bismuth
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Bonnin
authors.forename: Randy
authors.initials: R
authors.lastname: Johnson
authors.forename: Chen-Min
authors.initials: CM
authors.lastname: Fan
authors.forename: Frédéric
authors.initials: F
authors.lastname: Relaix
authors.forename: De-Li
authors.initials: DL
authors.lastname: Shi
authors.forename: Delphine
authors.initials: D
authors.lastname: Duprez
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D047369:Chromatin Immunoprecipitation; D018274:Electroporation; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D017570:MyoD Protein / Q000378:metabolism*; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019170:Somites / Q000196:embryology / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D014981:Xenopus
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C486578:Sim2 protein, mouse