EXPRESSION OF A RETINOBLASTOMA TRANSGENE RESULTS IN DWARF MICE

Introduction of the normal retinoblastoma gene (RB) into different tum or cells possessing inactivated RB genes suppresses their tumorigenici ty in nude mice. These results suggest that RB replacement is a potent ial strategy for developing future clinical treatments of cancer. In a transgenic mouse model, we found that the quantity of RB protein in a given cell may play an important role in dictating its effect. Four f ounder mice containing 1-7 copies of a human RB cDNA transgene under t he transcriptional control of the human RB promoter were generated. Mo st of the transgenic mice were smaller than nontransgenic littermates. This effect was found as early as embryonic day 15. The degree of dwa rfism correlated roughly with the copy number of the transgene and the corresponding level of RB protein. The expression pattern of the tran sgene products was similar to that of the endogenous mouse RB gene wit h regard to tissue and temporal distribution. Transferring the transge ne to RB deficient mice, which are nonviable, resulted in the developm ent of normal, healthy mice, indicating that the human RB gene can fun ctionally complement the mouse homolog. These studies demonstrate that the effect of RB on overall mouse development is closely dependent up on its dosage.