MyoD Meets Its Maker

Abstract

A model to account for the role of Pax-3 in myogenesis is shown in Figure 2Figure 2. Not surprisingly, these new studies on the myogenic functions of Pax-3 raise as many questions as they answer. For example, how does Pax-3 activate MyoD expression? Is the MyoD gene a direct target for transcriptional activation by Pax-3 or are there intermediate steps? MyoD transcription has been shown to be controlled by two distal upstream enhancers (9x.. Goldhammer, D.J., Faerman, A., Shani, M., and Emerson, C.P. Jr. . 1992; 256: 538–542See all References, 1x.. Asakura, A., Lyons, G.E., and Tapscott, S.J. Dev. Biol. 1995; 171: 386–398Crossref | PubMed | Scopus (82)See all References). A simple model would be that Pax-3 binds directly to one of these enhancers and activates MyoD transcription in collaboration with other enhancer-binding factors. However, since MyoD is expressed in only a subset of cells that express Pax-3, there must be other positive and negative cofactors that modulate the myogenic activity of Pax-3. What are the identities of such factors and what are their mechanisms of action? Pax-3 also has other functions in addition to regulating MyoD expression. What determines the sets of downstream genes regulated by Pax-3 in different cell types?Figure 2A Model for Regulatory Interactions in the Myogenic PathwayWnts and Shh produced by the neural tube and notochord, respectively, cooperate to induce Myf-5 and Pax-3 expression in the somites. Surface ectoderm also induces Myf-5 and MyoD expression. Myf-5 appears to regulate the early expression and Pax-3 the late expression of MyoD. Pax-3 also regulates c-Met expression, which is required for migration of muscle precursor cells to the limb bud. Myogenin acts downstream of MyoD and Myf-5 and is an essential activator of myogenesis in lateral and medial muscle lineages.View Large Image | View Hi-Res Image | Download PowerPoint SlideWhile there has been headway toward unraveling the mechanisms that regulate MyoD expression, little is known about the regulation of Myf-5. Does Pax-3 also play a role in Myf-5 regulation and what are the regulatory factors that control MyoD and Myf-5 expression in head muscle lineages? Moreover, what is the logic behind the existence of multiple apparently separate pathways for the formation of skeletal muscle when a single pathway would seem sufficient? Does this complexity simply expand the regulatory potential within these lineages or is there another reason? In this regard, what is the mechanism that allows one myogenic lineage to compensate for another or one genetic pathway to take over when another is absent?Finally, MyoD has been widely heralded as a “master regulator” of the myogenic lineage. A lesson from these studies is that being a master or a slave depends on the point of view.