PAX3 INHIBITS MYOGENIC DIFFERENTIATION OF CULTURED MYOBLAST CELLS

Pax3 is an evolutionarily conserved transcription factor expressed in the lateral dermomyotome, a region that gives rise to limb muscle prog enitors. Mutations in Pax-3 account for the mouse mutant Splotch which develops without limb musculature. We demonstrate that Pax3 can inhib it myogenic differentiation of C2C12 myoblasts normally induced by exp osure to low serum. Specific missense mutations that affect the DNA bi nding characteristics of the two distinct DNA binding domains of Pax3 abolish this effect. Furthermore, we show that Pax3 can inhibit myogen ic differentiation of 10T1/2 fibroblasts transfected with MyoD, but no t of 10T1/2 cells transfected with myogenin. This anti-myogenic proper ty is shared by a PAX3-forkhead fusion protein resulting from a t(2;13 ) chromosomal translocation found in pediatric alveolar rhabdomyosarco mas. These results suggest that Pax3 may suppress the terminal differe ntiation of migrating limb myoblasts and that the PAX3-forkhead fusion may contribute to the phenotype of alveolar rhabdomyosarcoma by preve nting terminal differentiation.