[Early stages of myogenesis as seen through the action of the myf-5 gene].

Abstract

Skeletal muscles in the vertebrate body are derived from the somites, epithelial spheres of cells which segment from the paraxial mesoderm in a rostral-caudal developmental gradient on either side of the neural tube. Initially, cells in the somite are multipotent and their fate depends on the environmental influences exerted by neighbouring tissues, notably the axial structures (neural tube and notochord), and the dorsal ectoderm. The ventralizing influence exerted by the notochord and floor plate of the neural tube through the action of sonic hedgehog, results in the differentiation of sclerotome which will give rise to cartilage and bone of the vertebral column and ribs. The dorsal derivatives of the somite, formed from cells in the dermomyotome, are derm and skeletal muscle. The onset of skeletal myogenesis is characterized by expression of myogenic factors, notably myf-5 and MyoD, members of the superfamily of helix-loop-helix transcription factors. Another member of the myogenic factor family, myogenin, is subsequently expressed and leads to muscle cell differentiation with activation of the downstream muscle-specific genes. Dorsalization of the somite and subsequent myogenesis depends on the presence of axial structures and dorsal ectoderm. The Wnt family of signalling molecules are potentially implicated in this process. Muscle progenitor cells present in the medial part of the dermomyotome activate myf-5 first and explant experiments have shown that the axial structures lead to the activation of this myogenic factor and subsequent myogenesis which results in the formation of the dorsal myotome in the central region of the somite. This contributes to the formation of axial muscles. Muscle progenitor cells in the lateral part of the dermomyotome preferentially activate MyoD and this depends on the presence of dorsal ectoderm. These cells will form the ventral aspect of the myotome, and later contribute to body wall muscles, for example. Part of the lateral progenitor population migrates away from the somite to form peripheral body muscles and the muscles of the limb. In this case myogenic factors are not initially expressed and these migratory cells are characterized by the expression of the paired-box gene Pax3. In explant experiments lateral mesoderm retards the induction of MyoD expression by dorsal ectoderm; in vivo this may be important to permit cell migration prior to differentiation. In mice carrying mutations in both MyoD and myf-5 no skeletal muscle forms, whereas myogenesis can take place in the absence of either MyoD or myf-5. Normally, cells in which one gene is activated first, subsequently co-express the other, so that there rapidly cease to be distinct MyoD+ or myf-5+ populations in the embryo. In myf-5-/- mice no myotome forms initially, but MyoD is subsequently activated. This takes place medially, as well as laterally, under the influence of the more mature neural tube and notochord. By targetting the myf-5 gene with an nlacZ reporter gene it has been possible to follow the fate of the early muscle progenitor cell population in which the myf-5 gene has been activated but no myf-5 protein is present. These beta-galactosidase positive cells delaminate from the dermomyotome, but instead of migrating under this epithelium to form the myotome, they migrate aberrantly. Some cells localize dorsally under the epiderm and begin to express the dermal marker, Dermo-1. Other muscle progenitor cells migrate ventrally into the sclerotomal compartment where they express an early sclerotomal marker, scleraxis. Later in the mutant mice, when cells from this compartment have condensed to form the cartilage of the ribs, beta-galactosidase positive cells are detectable within the ribs. These observations indicate that the early myogenic factor myf-5 is necessary to ensure the correct positioning of myogenic progenitor cells within the embryo. (ABSTRACT TRUNCATED)