The gene responsible for neurofibromatosis type 1 (NF1) has sequence homology to the GTPase-activating protein (GAP) and demonstrates GAP activity against ras p21. To study tissue-specific and/or tumor-specific expression of the NF1 gene product, now called neurofibromin, immunostaining and immunoblotting were applied to the N-nitroso-N-ethylurea (ENU)-induced Syrian hamster neurofibromatosis model using polyclonal antibodies against the NF1 fusion protein and a synthetic peptide. Strong expression was observed specific to the Schwann cells of the normal peripheral nerves by immunostaining. Neoplastic Schwann cells showed specific binding of anti-NF1; however, the frequency of positive cells was diminished. Immunoblotting also revealed positive expression of the 250-kd NF1 gene product in the brain, the normal peripheral nerves, and 7 of 14 ENU-induced neurofibromas. Although ENU-induced melanoma and Wilms' tumor were negative for neurofibromin, foci of Schwannian differentiation in both primary and transplanted melanomas were positive. These results suggest that neurofibromin plays some role in differentiation and growth regulation of the Schwann cell.