ANALYSIS OF THE ROLE OF THE RETINOBLASTOMA SUSCEPTIBILITY GENE IN MURINE DEVELOPMENT AND TUMORIGENESIS

Studies on the retinoblastoma susceptibility gene (RB) have played a central role in the conceptual development of the tumor suppressor gene field. Patients inheriting a mutation in the RB gene develop the rare pediatric eye cancer retinoblastoma with 90 % penetrance. In addition, somatic mutations in the RB gene have been found in many sporadically occurring human tumors. A great deal of insight has also been gained from studies of retinoblastoma protein (pRB) in tissue culture. These studies have shown that the protein product plays an important role in cell cycle coordination, perhaps by modulating some aspect of the restriction point during the G 1 phase of the cell cycle. Despite this vast amount of information, until recently very little was known about the normal function of RB in development. Techniques developed in the last decade have allowed mice with targeted mutations to be created. Several groups have exploited these techniques to create mice with germline inactivating mutations in the murine version of the retinoblastoma susceptibility gene (Rb). Initial analysis of these mice indicated that heterozygotes did not develop retinoblastoma, instead they develop tumors in the intermediate lobe of the pituitary and in the thyroid. Mice homozygous for the mutant allele die between 13.5 and 15.5 days of gestation wit