p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step

Cell-cycle arrest is thought to be required for differentiation of muscle c ells. However, the molecules controlling cell-cycle exit and the differenti ation step(s) dependent on cell-cycle arrest are poorly understood. Here we show that two Cdk inhibitors, p21(CIP1) and p57(KIP2), redundantly control differentiation of skeletal muscle and alveoli in the lungs. Mice lacking both p21 and p57 fail to form myotubes, display increased proliferation and apoptotic rates of myoblasts, and display endoreplication in residual myot ubes. This point of arrest during muscle development is identical to that o f mice lacking the myogenic transcription factor myogenin, indicating a rol e for cell-cycle exit in myogenin function. Expression of myogenin, p21, an d p57 is parallel but independent, and in response to differentiation signa ls, these proteins are coordinately regulated to trigger both cell-cycle ex it and a dependent muscle-specific program of gene expression to initiate m yoblast terminal differentiation and muscle formation.