TARGETED DISRUPTION OF P107 - FUNCTIONAL OVERLAP BETWEEN P107 AND RB

To explore the physiological role of p107, a member of retinoblastoma gene (Rb) family, we disrupted the mouse gene by homologous recombinat ion in embryonic stem cells. p107 homozygous mutant mice were viable, fertile, and displayed no obvious abnormalities. To investigate possib le functional overlap between p107 and Rb, mice with mutations at both loci were generated. Rb-+/-;p107(-/-) mice have a pronounced growth r etardation and increased mortality rate during the first 3 weeks after birth. The Rb-+/-;p107(-/-) pups that survive to adulthood did not sh ow any altered tumor predisposition when compared with Rb-+/- mice but developed multiple dysplastic lesions of the retina. Embryos homozygo us for both Rb and p107 died at similar to 11.5 days of gestation, 2 d ays earlier than embryos homozygous for Rb alone. Histological examina tion revealed accelerated apoptosis in the liver and the central nervo us system of Rb--/-;p107(-/-) embryos relative to Rb--/- embryos. Thes e results provide the first in vivo evidence that p107 and Rb have ove rlapping functions in some tissues of the developing and adult mouse.