P53-DEPENDENT APOPTOSIS PRODUCED BY RB-DEFICIENCY IN THE DEVELOPING MOUSE LENS

THE retinoblastoma tumour-suppressor gene (RB) has been implicated in negative growth regulation, induction of differentiation, and inhibition of cellular transformation(1). Homozygous inactivation of the Rb gene in the mouse leads to mid-gestational lethality with defects in erythropoiesis and neurogenesis(2-4). Here we describe the effects of the Rb-deficient state on the development of the ocular lens. The regional compartmentalization of growth, differentiation and apoptosis in the developing lens provides an ideal system to examine more closely the relationships of these processes in vivo. We demonstrate that loss of Rb function is associated with unchecked proliferation, impaired expression of differentiation markers, and inappropriate apoptosis in lens fibre cells. In addition, we show that ectopic apoptosis in Rb-deficient lenses is dependent on p53, because embryos doubly null for Rb and p53 show a nearly complete suppression of this effect. This developmental system provides a framework for understanding the consequences of the frequent mutation of both RB and p53 in human cancer.