Strain-Dependent Myeloid Hyperplasia, Growth Deficiency, and Accelerated Cell Cycle in Mice Lacking the Rb-Related p107 Gene

ABSTRACT

To investigate the function of the Rb-related p107gene, a null mutation in p107 was introduced into the germ line of mice and bred into a BALB/cJ genetic background. Mice lackingp107 were viable and fertile but displayed impaired growth, reaching about 50% of normal weight by 21 days of age. Mutant mice exhibited a diathetic myeloproliferative disorder characterized by ectopic myeloid hyperplasia in the spleen and liver. Embryonicp107^−/− fibroblasts and primary myoblasts isolated from adult p107 ^−/− mice displayed a striking twofold acceleration in doubling time. However, cell sort analysis indicated that the fraction of cells in G₁, S, and G₂ was unaltered, suggesting that the different phases of the cell cycle in p107 ^−/− cells was uniformly reduced by a factor of 2. Western analysis of cyclin expression in synchronized p107 ^−/− fibroblasts revealed that expression of cyclins E and A preceded that of D1. Mutant embryos expressed approximately twice the normal level of Rb, whereas p130 levels were unaltered. Lastly, mutant mice reverted to a wild-type phenotype following a single backcross with C57BL/6J mice, suggesting the existence of modifier genes that have potentially epistatic relationships with p107. Therefore, we conclude thatp107 is an important player in negatively regulating the rate of progression of the cell cycle, but in a strain-dependent manner.