Neurofibromatosis type I and II (NF1 and NF2) are human genetic diseases affecting the nervous system. In both diseases, individuals inherit a loss-of-function mutation in a tumor suppressor gene and are thereby predisposed to the development of a characteristic set of lesions. We have generated mouse strains carrying germline mutations in the murine homologues of the NF1 and NF2 genes. These strains have been used to date to evaluate the tumor phenotype caused by individual mutations in these genes as well as the effect of combined mutations in different tumor suppressor genes, the developmental requirements for Nf1 and Nf2 function, the phenotype of chimeric mice composed in part of cells lacking Nf1 or Nf2, and the effects of Nf1- and Nf2- deficiency in cells in culture.

In the present proposal, we will further our characterization of these strains (and cells derived from them) with the goal of understanding the growth control pathways regulated by these two genes, identifying genes that can modify the tumor phenotype caused by Nf1 or Nf2 mutation, improving their accuracy as disease models, and validating their use in screening potential therapeutic compounds. Disease development, tumor treatment, and genetic analysis will be performed at the level of the whole animal, either in germline mutants, chimeras, or both. We will also characterize the growth properties of Nf1- and Nf2- deficient mouse embryo fibroblasts and Nf2-/- tumor cell lines, as a prelude to gene reintroduction experiments and structure/function analysis. These experiments will be performed by a yeast artificial chromosome approach in the case of Nf1 and by regulated gene expression for Nf2. The purpose of this research is to determine the normal functions of Nf1 and Nf2, so as to understand the consequences of their mutation in disease. In addition, existing mutant phenotypes in the mouse can be used to test (and to design) potential therapies.