SHARED ROLE OF THE PRB-RELATED P130 AND P107 PROTEINS IN LIMB DEVELOPMENT

The p130 protein shares extensive sequence similarity with pRB, the pr oduct of the retinoblastoma gene, and is a major E2F-associated protei n in quiescent cells. To investigate its biological function, we have mutated p130 via gene targeting in the mouse. Homozygous mutation of p 130 had little discernible effect on development or on the growth of m ouse embryo fibroblasts in culture. Much of the E2F activity that norm ally associates with p130 in serum-starved mouse embryo fibroblasts as sociated instead with the highly related p107 protein. To determine wh ether p130 and p107 have overlapping biological roles, we produced mic e having simultaneous inactivation of the p130 and p107 genes. Such mi ce exhibited deregulated chondrocyte growth, defective endochondral bo ne development, shortened limbs, and neonatal lethality. These finding s indicate that p130 and p107 play an important role in limb developme nt through their abilities to control chondrocyte proliferation. Thus, in certain settings p107 and p130 perform growth-regulatory functions that are not fulfilled by pRB.