SCHWANN-CELLS FROM NEUROFIBROMIN DEFICIENT MICE EXHIBIT ACTIVATION OFP21(RAS), INHIBITION OF CELL-PROLIFERATION AND MORPHOLOGICAL-CHANGES

Schwann cells are thought to be abnormal in type 1 neurofibromatosis ( NF1) and to contribute to the formation of benign and malignant tumors in this disease. To test the role of the NF1 gene product neurofibrom in as a Ras-GTPase activating protein in Schwann cells, and to study t he effect of the loss of neurofibromin on Schwann cell. proliferation, we isolated Schwann cells from mice with targeted disruption of NET. The properties of these neurofibromin deficient cells were strikingly similar to those of v-ras expressing rat Schwann cells with normal lev els of neurofibromin. The similarities included: growth inhibition, no ted as a decrease in cell division in response to glial growth factor 2 (GGF2) and of neuronal contact; morphological changes such as the ap pearance of elaborated processes; and elevated levels of Ras-GTP, Furt hermore, Ras-GTP levels in the neurofibromin deficient Schwann cells w ere consistently elevated in response to GGFZ treatment. In contrast t o these results, introduction of v-ras into a Schwannoma cell line (RN 22) led to cell transformation. We conclude that neurofibromin functio ns as a major regulator of Ras-GTP in Schwann cells; however, mutation in NF1 by itself is unlikely to explain the hyperplasia observed in S chwann cell tumors in NF1 disease.