The First Knockout Mouse Model of Retinoblastoma

The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene identified in humans (Friend, et al., 1986) and the first tumor suppressor gene knocked out by targeted deletion in mice (Jacks, et al., Clarke, et al., Lee, et al., 1992). Children with a germline mutation in one of their RB1 alleles are likely to experience bilateral multifocal retinoblastoma; however, mice with a similar disruption of Rb1 do not develop retinoblastoma. The absence of a knock-out mouse model of retinoblastoma has slowed the progress toward developing new therapies and identifying secondary genetic lesions that occur after disruption of the Rb signaling pathway. Several advances have been made, over the past several years, in our understanding of the regulation of proliferation during retinal development (Zhang, et al., 2004; Dyer J, 2004; Dyer, Cepko, 2001) and we have built upon these earlier studies to generate the first nonchimeric knock-out mouse model of retinoblastoma. These mice are being used as a preclinical model to test new therapies for retinoblastoma and to elucidate the downstream genetic events that occur after inactivation of Rb1 or its related family members.