P107 IS A SUPPRESSOR OF RETINOBLASTOMA DEVELOPMENT IN PRB-DEFICIENT MICE

Hemizygosity for the retinoblastoma gene RE in man strongly predispose s to retinoblastoma. In the mouse, however, Rb hemizygosity leaves the retina normal, whereas in Rb-/- chimeras pRb-deficient retinoblasts u ndergo apoptosis. To test whether concomitant inactivation of the Rb-r elated gene p107 is required to unleash the oncogenic potential of pRb deficiency in the mouse retina, we inactivated both Rb and p107 by ho mologous recombination in embryonic stem cells and generated chimeric mice. Retinoblastomas were found in five out of seven adult pRb/p107-d eficient chimeras. The retinal tumors showed amacrine cell differentia tion, and therefore originated from cells committed to the inner but n ot the outer nuclear layer. Retinal lesions were already observed at e mbryonic day 17.5. At this stage, the primitive nuclear layer exhibite d severe dysplasia, including rosette-like arrangements, and apoptosis . These findings provide formal proof for the role of loss of Rb in re tinoblastoma development in the mouse and the first in vivo evidence t hat p107 can exert a tumor suppressor function.