Regulation of Muscle Differentiation by the MEF2 Family of MADS Box Transcription Factors

Abstract

INTRODUCTION tube gives rise to muscle precursors that form the myotome, the origin of the vertebral and back muscles. Cells from the ventrolateral edge of the dermamyotome migrate out There has been dramatic progress in recent years toward to form the muscles of the limbs and body wall. understanding the molecular mechanisms that regulate Cardiac muscle arises from cells in the anterior lateral skeletal muscle development. In contrast, relatively little plate mesoderm, which become committed to a cardiogenic is known of the mechanisms that give rise to cardiac and fate soon after gastrulation. These precardial cells give rise smooth muscle during embryogenesis. These different musto a heart tube, which undergoes looping, followed by forcle cell types express many of the same muscle-specific mation of the atria and ventricles. genes. However, they are each unique in several respects, In contrast to skeletal and cardiac muscle, which arise including the spectrum of muscle isoforms expressed, morfrom distinct populations of mesodermal precursors, phology, contractile properties, and ability to divide. In prinsmooth muscle arises throughout the embryo from different ciple, the expression of muscle genes in skeletal, cardiac, populations of mesenchymal cell precursors, as well as from and smooth muscle cells could be controlled by a shared the neural crest (Miano et al., 1994). Among the three major myogenic regulatory program, which is modified within muscle cell types, the least is known about the mechanisms each lineage to confer the unique identities of each muscle that control muscle gene expression in smooth muscle cells. cell type. Alternatively, there could be myogenic regulatory factors unique to each myogenic lineage, which act through different cis-acting DNA sequences to activate muscle structural genes. This review will consider recent evidence Regulation of Muscle Differentiation by Myogenic that suggests the existence of a common myogenic program, bHLH Proteins controlled by the myocyte enhancer factor-2 (MEF2) family Much of our knowledge of skeletal muscle development of MADS box transcription factors. has come from the discovery of the MyoD family of basic helix-loop-helix (bHLH) proteins, which can activate skeleEmbryonic Origins of the Three Muscle Cell Types tal muscle gene expression when expressed ectopically in nonmuscle cell types (reviewed in Olson, 1990; Weintraub During vertebrate embryogenesis, skeletal, cardiac, and et al., 1991; Rudnicki and Jaenisch, 1995). There are four smooth muscle cells arise from distinct mesodermal precurmembers of this family in vertebrate species, MyoD, Myosors in different regions of the embryo (Fig. 1). Skeletal musgenin, Myf5, and MRF4, which share extensive amino acid cle is derived from the somites, which form by segmentahomology within their bHLH regions. During embryogenetion of the paraxial mesoderm lateral to the neural tube sis, the myogenic bHLH factors show overlapping, but dis(Wachtler and Christ, 1992). The somites appear initially as tinct, expression patterns in the skeletal muscle lineage. epithelial spheres, which subsequently become compartMyf5 is the first member of the family to be expressed in the mentalized to form the dermamyotome and the sclerotome. mouse, appearing in the dorsomedial region of the rostral The region of the dermamyotome adjacent to the neural uncompartmentalized somites beginning at Day 8.0 post coitum (p.c.). Myogenin is expressed in the myotome about a half-day later and MRF4 and MyoD are expressed begin1 To whom correspondence should be addressed. Fax: (713) 7919478. ning at Days 9.5 and 10.5 p.c., respectively (reviewed in