AbstractIn this study, we have identified novel roles for Sox15 and Sox7 as regulators of muscle precursor cell fate in P19 cells. To examine the role of Sox15 and Sox7 during skeletal myogenesis, we isolated populations of P19 cells with either gene stably integrated into the genome, termed P19[Sox15] and P19[Sox7]. Both SOX proteins were sufficient to upregulate the expression of the muscle precursor markers Pax3/7, Meox1, and Foxc1 in aggregated cells. In contrast to the P19[Sox7] cell lines, which subsequently differentiated into skeletal muscle, myogenesis failed to progress past the precursor stage in P19[Sox15] cell lines, shown by the lack of MyoD and myosin heavy chain (MHC) expression. P19[Sox15] clones showed elevated and sustained levels of the inhibitory factors Msx1 and Id1, which may account for the lack of myogenic progression in these cells. Stable expression of a Sox15 dominant-negative protein resulted in the loss of Pax3/7 and Meox1 transcripts, as well as myogenic regulatory factor (MRF) and MHC expression. These results suggest that Sox15, or genes that are bound by Sox15, are necessary and sufficient for the acquisition of the muscle precursor cell fate. On the other hand, knockdown of endogenous Sox15 caused a decrease in Pax3 and Meox1, but not MRF expression, suggesting that other factors can compensate in the absence of Sox15. Taken together, these results show that both Sox7 and Sox15 are able to induce the early stages of myogenesis, but only Sox7 is sufficient to initiate the formation of fully differentiated skeletal myocytes.Disclosure of potential conflicts of interest is found at the end of this article.