A 4TH HUMAN MEF2 TRANSCRIPTION FACTOR, HMEF2D, IS AN EARLY MARKER OF THE MYOGENIC LINEAGE

The transition from multipotent mesodermal precursor to committed myob last and its differentiation into a mature myocyte involve molecular e vents that enable the cell to activate muscle-specific genes. Among th e participants in this process is the myocyte-specific enhancer factor 2 (MEF2) family of tissue-restricted transcription factors. These fac tors, which share a highly conserved DNA-binding domain including a MA DS box, are essential for the expression of multiple muscle genes with cognate target MEF2 sites in cis. We report here a new human MEF2 fac tor, hMEF2D, which is unique among the members of this family in that it is present not only in myotubes but also in undifferentiated myobla sts, even before the appearance of myogenin. hMEF2D comprises several alternatively spliced products of a single gene, one of which is the h uman homolog of the Xenopus SRF-related factor SL-1. Like its relative s, cloned hMEF2D is capable of activating transcription via sequence-s pecific binding to the MEF2 site, recapitulating endogenous tissue-spe cific MEF2 activity. Indeed, while MEF2D mRNAs are ubiquitous, the pro tein is highly restricted to those cell types that contain this activi ty, implicating posttranscriptional mechanisms in the regulation of ME F2D expression. Alternative splicing may be important in this process: two alternative MEF2D domains, at least one of which is specifically included during myogenic differentiation, also correlate precisely wit h endogenous MEF2 activity. These findings provide compelling evidence that MEF2D is an integral link in the regulatory network for muscle g ene expression. Its presence in undifferentiated myoblasts further sug gests that it may be a mediator of commitment in the myogenic lineage.