Mice lacking the imprinted Cdk inhibitor p57(KIP2) have altered cell proliferation and differentiation, leading to abdominal muscle defects; cleft palate; endochondral bone ossification defects with incomplete differentiation of hypertrophic chondrocytes; renal medullary dysplasia; adrenal cortical hyperplasia and cytomegaly; and lens cell hyperproliferation and apoptosis. Many of these phenotypes are also seen in patients with Beckwith-Wiedemann syndrome, a pleiotropic hereditary disorder characterized by overgrowth and predisposition to cancer, suggesting that loss of p57(KIP2) expression may play a role in the condition.

Cell-cycle arrest is thought to be required for differentiation of muscle cells. However, the molecules controlling cell-cycle exit and the differentiation 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 myotubes. This point of arrest during muscle development is identical to that of mice lacking the myogenic transcription factor myogenin, indicating a role for cell-cycle exit in myogenin function. Expression of myogenin, p21, and p57 is parallel but independent, and in response to differentiation signals, these proteins are coordinately regulated to trigger both cell-cycle exit and a dependent muscle-specific program of gene expression to initiate myoblast terminal differentiation and muscle formation. Embryonic development is a complex process that requires precise spatial and temporal control of cell proliferation coordinated together with differentiation, morphogenesis, and pattern formation. Cell proliferation in the embryo is controlled by an intricate network of signal transduction pathways that integrate growth regulatory signals through regulation of cyclin-dependent kinases (Cdks), a family of enzymes that catalyze events required for cell-cycle transitions. Primary targets for this regulation are the G 1 cyclin/Cdk complexes cyclin D/Cdk4 and cyclin E/Cdk2, which cooperate to control the G 1 → S transition through phosphorylation and inactivation of the retinoblastoma (Rb) protein. Among other functions, Rb acts as a transcriptional repressor of E2F-regulated genes important for cell proliferation (Weinberg 1995). A large number of regulatory mechanisms exist to modulate Cdk activity, reflecting the complexity of the signaling pathways involved and the necessity to precisely control proliferation for the development of an organism. A particularly versatile mechanism for developmental control is the inhibition of Cdks by cyclin-dependent kinase inhibitors (CKIs), of which there are two families: the p16 INK4a family, including p15, p16, p18, and p19; and the p21 CIP1/WAF1 family, including p21, p27, and p57 (Harper and Elledge 1996). The p16 family specifically inhibits Cdk4 and Cdk6, whereas the p21 family inhibits all Cdks involved in G 1 /S transition. The roles of these CKIs in development and in cancer have been revealed through targeted gene inactivation in mice. Although CKIs show striking tissuespecific patterns of expression during development, surprisingly only p57 loss has been shown to have a significant role in multiple tissues during embryonic development, suggesting that the other inhibitors are either not required or are redundant. Loss of p57 in humans results in the complex overgrowth and cancer predisposition disease Beckwith-Wiedemann syndrome (Zhang et al. 1997).A variety...

The mammalian F-box protein Fbw7 and its Caenorhabditis elegans counterpart Sel-10 have been implicated in the ubiquitin-mediated turnover of cyclin E as well as the Notch͞Lin-12 family of transcriptional activators. Both unregulated Notch and cyclin E promote tumorigenesis, and inactivating mutations in human Fbw7 suggest that it may be a tumor suppressor. To generate an in vivo system to assess the consequences of such unregulated signaling, we generated mice deficient for Fbw7. Fbw7-null mice die around 10.5 days post coitus because of a combination of deficiencies in hematopoietic and vascular development and heart chamber maturation. The absence of Fbw7 results in elevated levels of cyclin E, concurrent with inappropriate DNA replication in placental giant trophoblast cells. Moreover, the levels of both Notch 1 and Notch 4 intracellular domains were elevated, leading to stimulation of downstream transcriptional pathways involving Hes1, Herp1, and Herp2. These data suggest essential functions for Fbw7 in controlling cyclin E and Notch signaling pathways in the mouse.