Embryonic skeletal muscle development has become a paradigm for understanding the molecular basis of how cell lineages are established and how cells differentiate into specialized structures. Most vertebrate muscles are derived from individual somites that produce two distinct muscle populations: the myotomal muscles that generate the axial and trunk musculature and a second migratory cell population that colonizes regions of the developing limbs. In both instances, muscle differentiation is accompanied by cell cycle arrest, fusion of individual myoblasts into multinucleate myotubes, and the transcriptional activation of muscle-specific genes. Recent experimental progress has led to greater understanding of the molecular mechanisms that control myogenesis in the embryo. Most of the advances have come from the identification and isolation of regulatory genes that are involved in controlling specific transcriptional events. In particular, the muscle regulatory factor (MRF) and myocyte enhancer factor 2 (MEF2) families have been implicated in establishing the myogenic lineage as well as controlling terminal differentiation. Two additional transcription factors, Pax-3 and MLP, also appear to play a role in the production of a mature muscle cell. This review focuses on these four vertebrate transcription factor families and discusses the experimental evidence that these factors play important, non-overlapping roles in regulating skeletal muscle development.

The basic helix-loop-helix muscle regulatory factor (MRF) gene family encodes four distinct muscle-specific transcription factors known as MyoD, myogenin, Myf-5, and MRF4. These proteins represent key regulatory factors that control many aspects of skeletal myogenesis. Although the MRFs often exhibit overlapping functional activities, their distinct expression patterns during embryogenesis suggest that each protein plays a unique role in controlling aspects of muscle development. As a first step in determining how MRF4 gene expression is developmentally regulated, we examined the ability of the MRF4 gene to be expressed in a muscle-specific fashion in vitro. Our studies show that the proximal MRF4 promoter contains sufficient information to direct muscle-specific expression. Located within the proximal promoter are a single MEF2 site and E box that are required for maximum MRF4 expression. Mutation of the MEF2 site or E box severely impairs the ability of this promoter to produce a muscle-specific response. In addition, the MEF2 site and E box function in concert to synergistically activate the MRF4 gene in nonmuscle cells coexpressing MEF2 and myogenin proteins. Thus, the MRF4 promoter is regulated by the MEF2 and basic helix-loop-helix MRF protein family through a cross-regulatory circuitry. Surprisingly, the MRF4 promoter itself is not transactivated by MRF4, suggesting that this MRF gene is not subject to an autoregulatory pathway as previously implied by other studies. Understanding the molecular mechanisms regulating expression of each MRF gene is central to fully understanding how these factors control developmental events.

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