Use of NF1 and NF2 Mutant Mouse Strains in the Investigation of Gene Function and Disease Development

摘要

Mouse strains carrying germline mutations in the NFl and NF2 tumor suppressor genes have been used as mouse models for human neurofibromatosis types 1 and 2. Progress over the past 3 years has included the generation of three mouse models of NF1. These models include a chimeric model, which develops benign neurofibromas; a combined germline NFl/p53 mutant model that develops MPNSTs; and a combined NFl/p53 mutant model that develops astrocytomas. Through biochemical analysis of the Nfl gene product we have identified a mechanism by which neurofibromin is regulated, the sequences responsible for this regulation, and the role of neurofibromin in attenuating the Ras/MAP kinase pathway in MEFs. Genetic modifier screens using the NFl/p53 mice on different inbred strain combinations have been performed. All Fl strain combinations show significant differences in tumor latency and/or tumor spectra when compared to the B6 parental strain. In addition, different backcross strains are being generated to identify modifier genes. Progress is reported toward the development of an in vitro kinase assay for the isolation of a kinase responsible for phosphorylating the Nf2 gene product, merlin. Finally, Nf2 conditional expression systems have been developed to assess Nf2 function in growth control, tumor suppression, and cell survival.