p57 Kip2 is a paternally imprinted gene that encodes a potent inhibitor of several cyclin/Cdk complexes. p57 Kip2 is primarily expressed in terminally differentiated cells, associates with G 1 Cdks, and can cause cell cycle arrest in G1 phase. To investigate the role of p57 Kip2 in vivo, we have ablated the p57 rap2 gene by homologous recombination in ES cells and generated mice devoid of p57 KIp2 expression. Most p57 Kip2 null mice die after birth and display severe developmental defects with

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... arying degrees of penetrance. As expected, heterozygous mice that inherit a maternal, but not a paternal, targeted allele exhibit similar deficiencies and neonatal death. Developmental defects of p57 ~'2 mutant mice include cleft palate and gastrointestinal abnormalities ranging from an inflated GI tract to loss of the jejunum and ileum. These tissues display a significant increase of apoptotic cells in the absence of p57 Kip2. Most p57 ~:ip2 mutant mice have short limbs, a defect attributable to abnormal endochondral ossification caused by delayed cell cycle exit during chondrocyte differentiation. A similar defect has been observed in mice lacking p107 and p130, thus suggesting that p57 KIp2 might be an upstream regulator of these Rb-related proteins. The p57 mp2 locus has been implicated in the Beckwith-Wiedemann syndrome and in the development of sporadic Wilms' tumors and lung carcinomas. To date, we have not observed neoplastic development even in those p57 KIp2 mutant mice that have survived for >5 months of age. These findings indicate that p57 Kip2 has an important role during mouse development that cannot be compensated by other Cdk inhibitors.