title: The early epaxial enhancer is essential for the initial expression of the skeletal muscle determination gene Myf5 but not for subsequent, multiple phases of somitic myogenesis.
abstract: Vertebrate myogenesis is controlled by four transcription factors known as the myogenic regulatory factors (MRFs): Myf5, Mrf4, myogenin and MyoD. During mouse development Myf5 is the first MRF to be expressed and it acts by integrating multiple developmental signals to initiate myogenesis. Numerous discrete regulatory elements are involved in the activation and maintenance of Myf5 gene expression in the various muscle precursor populations, reflecting the diversity of the signals that control myogenesis. Here we focus on the enhancer that recapitulates the first phase of Myf5 expression in the epaxial domain of the somite, in order to identify the subset of cells that first transcribes the gene and therefore gain insight into molecular, cellular and anatomical facets of early myogenesis. Deletion of this enhancer from a YAC reporter construct that recapitulates the Myf5 expression pattern demonstrates that this regulatory element is necessary for expression in the early epaxial somite but in no other site of myogenesis. Importantly, Myf5 is subsequently expressed in the epaxial myotome under the control of other elements located far upstream of the gene. Our data suggest that the inductive signals that control Myf5 expression switch rapidly from those that impinge on the early epaxial enhancer to those that impinge on the other enhancers that act later in the epaxial somite, indicating that there are significant changes in either the signalling environment or the responsiveness of the cells along the rostrocaudal axis. We propose that the first phase of Myf5 epaxial expression, driven by the early epaxial enhancer in the dermomyotome, is necessary for early myotome formation, while the subsequent phases are associated with cytodifferentiation within the myotome.
authors.affiliation: Division of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Teboul
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
authors.forename: Philippe
authors.initials: P
authors.lastname: Daubas
authors.forename: Dennis
authors.initials: D
authors.lastname: Summerbell
authors.forename: Margaret
authors.initials: M
authors.lastname: Buckingham
authors.forename: Peter W J
authors.initials: PW
authors.lastname: Rigby
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D017930:Genes, Reporter; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D024510:Muscle Development / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000502:physiology*; D051787:Myogenic Regulatory Factor 5; D019170:Somites; D015534:Trans-Activators; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D015534:Trans-Activators