Wnt1 and Wnt3a are signaling factors known to play a role in the induction of myogenesis in the myotome of the differentiating somite. Both factors may transduce their signal by a conserved pathway that leads to transcriptional regulation by beta-catenin/Lef1. beta-Catenin and Lef1 are found in the myotome prior to MyoD expression. We have utilized the P19 cell system to study the mechanisms by which Wnt3a may activate MyoD expression and subsequent skeletal muscle development. We have isolated P19 cell lines that stably express either Wnt3a or activated beta-catenin and found that aggregation of these cells results in the induction of myogenesis compared with control cells. Pax3, Gli2, Mox1, and Six1 were expressed during Wnt3a and beta-catenin-induced differentiation prior to MyoD expression. Furthermore, we have shown that the nuclear function of beta-catenin was essential for skeletal myogenesis in P19 cells by overexpression of a dominant negative beta-catenin/engrailed chimera. Primitive streak factors were present, but expression of Pax3, Mox1, Gli2, and Six1 was lost in these cells, indicating that nuclear beta-catenin is essential for specification of mesodermal precursors to the myogenic lineage. Therefore, Wnt signaling, acting via beta-catenin, is necessary and sufficient for skeletal myogenesis in P19 cells.