Skeletal muscle differentiation is mediated by a complex gene expression program
requiring both the muscle-specific transcription factor Myogenin (Myog) and p38α
MAPK (p38α) signaling. However, the relative contribution of Myog and p38α to the
formation of mature myotubes remains unknown. Here, we have uncoupled the
activity of Myog from that of p38α to gain insight into the individual roles of
these proteins in myogenesis. Comparative expression profiling confirmed that
Myog activates the expression of genes involved in muscle function. Furthermore,
we found that in the absence of p38α signaling, Myog expression leads to the
down-regulation of genes involved in cell cycle progression. Consistent with
this, the expression of Myog is sufficient to induce cell cycle exit.
Interestingly, p38α-defective, Myog-expressing myoblasts fail to form
multinucleated myotubes, suggesting an important role for p38α in cell fusion.
Through the analysis of p38α up-regulated genes, the tetraspanin CD53 was
identified as a candidate fusion protein, a role confirmed both ex vivo in
primary myoblasts, and in vivo during myofiber regeneration in mice. Thus, our
study has revealed an unexpected role for Myog in mediating cell cycle exit and
has identified an essential role for p38α in cell fusion through the
up-regulation of CD53.