MyoD Meets Its Maker

Alan Rawls and Eric N. Olson domains, the sclerotome, myotome, and dermomyotome. Initially, the ventral region of the somite acquires Department of Molecular Biology and Oncology The University of Texas Southwestern Medical Center a mesenchymal phenotype and forms the sclerotome, from which the ribs and vertebrae and derived. The dorat Dallas 6000 Harry Hines Boulevard sal half of the somite forms an epithelial sheet known as the dermomyotome. Cells from the anterior medial Dallas, Texas 75225-9149 edge of the dermomyotome adjacent to the neural tube invaginate to form the centrally located myotomal compartment of the somite. The dorsomedial half of the The discovery of the four myogenic basic helix-loophelix (bHLH) transcription factors MyoD, myogenin, myotome gives rise to the back (epaxial) muscles, while cells from the ventrolateral portion migrate ventrally to Myf-5, and MRF4, each of which can activate the program for skeletal muscle differentiation, has led to rapid form the body wall (hypaxial) muscles. At the limb levels, cells from the ventrolateral edge of the dermomyotome progress toward understanding the molecular mechanisms that regulate muscle gene expression (Molkentin migrate to the limb buds to form the limb musculature. The muscles of the head and neck are thought to be and Olson, 1996). However, what regulates the myogenic bHLH genes to initiate the pathway for skeletal derived from paraxial mesoderm anterior to the somites and from prechordal mesoderm. muscle development is a question that has continued to loom large in the field. In moving upstream in a regulaCells from the newly formed somite are initially multipotent and become committed to specific fates in tory pathway for cell type specificity, there must ultimately be non–cell type–specific factors that trigger response to instructive signals from surrounding cell types (Yun and Wold, 1996). Wnts, which are produced commitment to a particular lineage. The myogenic bHLH factors are the earliest markers specific for the skeletal by the dorsal neural tube and surface ectoderm, induce dermomyotome-specific gene expression, whereas muscle lineage in vertebrate embryos, but whether their expression signals the initiation of this developmental sonic hedgehog (Shh), secreted from the notochord and ventral floorplate of the neural tube, induces scleropathway or is preceded by an even earlier muscle-specific factor has not been previously determined. Two tome-specific gene expression, thereby excluding myogenic cells from this region of the somite. Expression papers in this issue of Cell begin to clarify these matters: using complementary approaches, the Buckingham and of myogenic genes in the myotome requires a combination of Wnts and Shh. In addition, an inhibitory signal Lassar labs (Tajbakhsh et al., 1997; Maroto et al., 1997 [both in this issue of Cell]) demonstrate that the paired(probably bone morphogenetic protein 4) produced by the lateral mesoderm prevents myogenesis. Thus, overtype homeobox gene Pax-3 is a key regulator of skeletal muscle development that is both necessary and suffilapping gradients of multiple signaling molecules result in specific patterns of gene expression throughout the cient (in certain cellular contexts) to activate MyoD expression and initiate the myogenic program in vivo and developing somite. How these signaling molecules activate the myogenic pathway (or any other somitic pathin vitro. Since Pax-3 is expressed in a wide range of cell types, it must act through combinatorial mechanisms way) is unknown, but the regulatory genes that specify the identity of the myogenic lineage must be exquisitely to control commitment to the myogenic lineage. Indeed, there is evidence suggesting the existence of positive sensitive to the concentrations of these secreted factors because myogenesis occurs in only a narrowly defined and negative regulators that dictate a cell’s responsiveness to the myogenic functions of Pax-3. subset of somitic cells. In the mouse, Myf-5 is the first of the myogenic bHLH It Starts in the Somites In vertebrates, all skeletal muscles with the exception of genes to be expressed, with transcripts appearing in myogenic precursor cells at the dorsomedial edge of the a few muscles in the head are derived from the somites, which form as transient epithelial spheres within the dermomyotome as they invaginate to form the myotome (Yun and Wold, 1996). Myogenin is expressed soon paraxial mesoderm flanking the neural tube (Christ and Ordahl, 1995) (Figure 1). As the somites mature, they thereafter, as myotomal cells begin to differentiate, and MyoD and MRF4 are expressed a day or two later. Cells become compartmentalized into three distinct cellular