Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene

The retinoblastoma-related p130 protein is a member of a conserved family, consisting of Rb, p107 and p130, which are believed to play important roles in cell-cycle control and cellular differentiation. We have generated a nu ll mutation in p130 by gene targeting and crossed the null allele into Balb /cJ and C57BL/6J strains of mice. In an enriched Balb/cJ genetic background , p130(-/-) embryos displayed arrested growth and died between embryonic da ys 11 and 13, Histological analysis revealed varying degrees of disorganiza tion in neural and dermamyotomal structures. Immunohistochemistry with anti body reactive with Islet-1 indicated markedly reduced numbers of neurons in the spinal cord and dorsal root ganglia, Immunohistochemistry with antibod y reactive with desmin indicated a similar reduction in the number of diffe rentiated myocytes in the myotome, The myocardium of mutant embryos was abn ormally thin and resembled an earlier staged two-chambered heart consisting of the bulbus cordis and the ventricular chamber. TUNEL analysis indicated the presence of extensive apoptosis in various tissues including the neura l tube, the brain, the dermomyotome, but not the heart. Immunohistochemistr y with antibody reactive with PCNA revealed increased cellular proliferatio n in the neural tube and the brain; and decreased proliferation in the hear t. The placentas of p130(-/-) embryos did not display elevated apoptosis an d were indistinguishable from wild type suggesting that the phenotype was n ot due to placental failure. Following a single cross with the C57BL/6 mice , p130(-/-) animals were derived that were viable and fertile. These result s indicate that p130 in a Balb/cJ genetic background plays an essential rol e that is required for normal development. Moreover, our experiments establ ish that second-site modifier genes exist that have an epistatic relationsh ip with p130.