The expression of Myf5 in the developing mouse embryo is controlled by discrete and dispersed enhancers specific for particular populations of skeletal muscle precursors.
The development of skeletal muscle in vertebrate embryos is controlled by a transcriptional cascade that includes the four myogenic regulatory factors Myf5, Myogenin, MRF4 and MyoD. In the mouse embryo, Myf5 is the first of these factors to be expressed and mutational analyses suggest that this protein acts early in the process of commitment to the skeletal muscle fate. We have therefore analysed the regulation of Myf5 gene expression using transgenic technology and find that its control is markedly different from that of the other two myogenic regulatory factor genes previously analysed, Myogenin and MyoD. We show that Myf5 is regulated through a number of distinct and discrete enhancers, dispersed throughout 14 kb spanning the MRF4/Myf5 locus, each of which drives reporter gene expression in a particular subset of skeletal muscle precursors. This region includes four separate enhancers controlling expression in the epaxial muscle precursors of the body, some hypaxial precursors of the body, some facial muscles and the central nervous system. These elements separately or together are unable to drive expression in the cells that migrate to the limb buds and in some other muscle subsets and to correctly maintain expression at late times. We suggest that this complex mechanism of control has evolved because different inductive signals operate in each population of muscle precursors and thus distinct enhancers, and cognate transcription factors, are required to interpret them.
Division of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK.
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Summerbell
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Ashby
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Coutelle
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Cox
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Yee
P W
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Rigby
D000818:Animals; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins; D005314:Embryonic and Fetal Development; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology*; D016296:Mutagenesis; D051787:Myogenic Regulatory Factor 5; D012045:Regulatory Sequences, Nucleic Acid; D019170:Somites; D015534:Trans-Activators; D019076:Transgenes
D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D015534:Trans-Activators