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 t hese factors to be expressed and mutational analyses suggest that this prot ein acts early in the process of commitment to the skeletal muscle fate. We have therefore analysed the regulation of Myf5 gene expression using trans genic technology and find that its control is markedly different from that of the other two myogenic regulatory factor genes previously analysed, Myog enin and MyoD, We show that Myf5 is regulated through a number of distinct and discrete enhancers, dispersed throughout 14 kb spanning the MRF4/Myf5 l ocus, 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 nervou s system. These elements separately or together are unable to drive express ion in the cells that migrate to the limb buds and in some other muscle sub sets and to correctly maintain expression at late times. We suggest that th is complex mechanism of control has evolved because different inductive sig nals operate in each population of muscle precursors and thus distinct enha ncers, and cognate transcription factors, are required to interpret them.