E2F1 and p53 are dispensable, whereas p21(Waf1/Cip1) cooperates with Rb torestrict endoreduplication and apoptosis during skeletal myogenesis

We describe temporal and genetic analyses of partially rescued Rb mutant fe tuses, mgRb:Rb-/-, that survive to birth and reveal specific defects in ske letal muscle differentiation. We show that in the absence of Rb, these fetu ses exhibit increased apoptosis, bona fide endoreduplication, and incomplet e differentiation throughout terminal myogenesis. These defects were furthe r augmented in composite mutant fetuses, mgRb:Rb-/-:p21-/-, lacking both Rb and the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Although E2F1 an d p53 mediate ectopic DNA synthesis and cell death in several tissues in Rb mutant embryos, both endoreduplication and apoptosis persisted in mgRb:Rb- /-:E2F1-/- and mgRb:Rb-/-:p53-/- compound mutant muscles. Thus, combined in activation of Rb and p21(Waf1/Cip1) augments endoreduplication and apoptosi s, whereas E2F1 and p53 are dispensable during aberrant myogenesis in Rb-de ficient fetuses. (C) 2000 Academic Press.