EXTENSIVE CONTRIBUTION OF RB-DEFICIENT CELLS TO ADULT CHIMERIC MICE WITH LIMITED HISTOPATHOLOGICAL CONSEQUENCES

Homozygosity for a mutation in the Rb tumor suppresser gene causes mid -gestation embryonic lethality in the mouse. Using a two-step targetin g protocol, we have constructed Rb homozygous mutant mouse embryonic s tem cells and used them to create chimeric animals partially composed of Rb-deficient cells. Analysis of these chimeras demonstrates widespr ead contribution of the mutant cells to adult tissues, including the r etina and mature erythrocytes. Despite the presence of large numbers o f Rb-deficient cells in most tissues of these mice, they are remarkabl y normal but do exhibit certain histological defects including catarac ts, hyperplasia of the adrenal medulla, and enlarged cells in the cere bellum and the liver. Like animals heterozygous for the Rb mutation, t he chimeras develop tumors of the intermediate lobe of the pituitary, and the rate of pituitary tumorigenesis is greatly accelerated.