REDEFINING THE GENETIC HIERARCHIES CONTROLLING SKELETAL MYOGENESIS - PAX-3 AND MYF-5 ACT UPSTREAM OF MYOD

We analyzed Pax-3 (splotch), Myf-5 (targeted with nlacZ), and splotch/ Myf-5 homozygous mutant mice to investigate the roles that these genes play in programming skeletal myogenesis. In splotch and Myf-5 homozyg ous embryos, myogenic progenitor cell perturbations and early muscle d efects are distinct. Remarkably, splotch/Myf-5 double homozygotes have a dramatic phenotype not seen in the individual mutants: body muscles are absent. MyoD does not rescue this double mutant phenotype since a ctivation of this gene proves to be dependent on either Pax-3 or Myf-5 . Therefore, Pax-3 and Myf-5 define two distinct myogenic pathways, an d MyoD acts genetically downstream of these genes for myogenesis in th e body. This genetic hierarchy does not appear to operate for head mus cle formation.