The Use of NF1 and NF2 Mutant Mouse Strains in the Investigation of Gene Function and Disease Development
Abstract
Mouse strain carrying germline mutations in the Nfl and Nf2 tumor suppressor genes have been used as mouse models of human neurofibromatosis types 1 and 2, and cells derived from these mice have been used to address the normal functions of the Nfl and Nf2 genes. Progress over the past year has included the completion and publication of two mouse models of Nf1: a chineric model which develops benign neurofibrones and a combined germline Nfl/p53 mutant model that develops MPNSTs. Genetic modifier screens using the Nfl/p53 model have proceeded to the point of identifying strain-specific differences in tumor latency and tumor spectrum in some strain combinations. Predisposition to astrocytona in these nice was also discovered in the course of this analysis. Biochemical analysis of the Nfl gene product, neurofibromin, has shown that is rapidly degraded following mitogenic stimulation, in a PKC-dependent manner. This process appears to limit the strength and duration of the Ras pathway signaling. Cell biological studies have implicated Nf2 in the regulation of the Racl pathway, and Racl also stimulates the phosphorylation of the Nf2 product, merlin. Progress is reported toward the isolation of the Red-stimulated merlin kinase. Finally, conditional expression systems are being developed to express Nf2 in a number cell types to assess its function in growth control, tumor suppression and cell survival.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1999
- Accession Number
- ADB262474
Entities
People
- Tyler Jacks
Organizations
- Massachusetts Institute of Technology