Proliferative myocytes precuursor cells migrate from the somite and fuse to form distinct groups of post-mitotic myotubes in the trunk and limbs. Myocyte differntiation is characterized by an ordered progression through discrete developmental steps. Cell cycle exit occurs early during the differntiation program and it it essential for normal expression of the contractile phenotype. In contrast to precursor cells, differentiated myocytes display a markedly lower frequency of apoptotic cell death. Previous studies have shown that the upregulation of the cdk inhibitor p21 and the dephosphorylation of pRb appear to be criitical regulatory events for the establishment of both the post-mitotic and apoptosis-resistant states in vitro and in vivo. However, the mechanisms that coordinate cell cycle activity and apoptosis are largely unknown. The purpose of this proposed research is totest the hypothesis that the Art kinases (Akt and Akt2) play important roles in regulating the survival of differentiating myocytes. Specifically, we will test whether Akt kinases are regulated by developmental cues during myogenesis with consequences on cell survival. We will also test whether the induction of Akt during mycyte differentiation is inhibited by cell cycle activity in a manner similar to contractile protein genes. Finally, we will examine the temporal and spatial patterns of Akt and Akt2 peptide expression in the developing mouse embryo and determine the mechanisms relating Akt and Akt2 induction during muscle differentiation. Collectively, thesee experiments will explore the hypothesis that myocyte survival and proliferation are coordinately regulated through the ability of cell cycle activity to modulate the myogenic induction of Akt and/or Akt2.
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