Individuals with neurofibromatosis type 1 (NF1) carry mutations in the NF1 tumor suppressor and develop benign peripheral nerve sheath tumors called neurofibromas. Neurofibromas contain normal nerve constituents: axons, Schwann cells, fibroblasts, and mast cells, as well as increased numbers of mast cells, excessive collagen, and Schwann cells free of axons. Tumorigenesis results from complete loss of function at NF1, as neurofibromas are characterized by biallelic mutations in tumor Schwann cells. Other cell types may be recruited secondarily. We developed a mouse model system for Schwann cell tumorigenesis in NF1, and identified aberrant expression of epidermal growth factor receptor in this model. EGFR also shows increased expression in human tumor samples. We expressed EGFR in transgenic mouse Schwann cells reproducing early phases of neurofibroma formation in mice including Schwann cell migration from axons, attraction of mast cells to peripheral nerve, and fibrosis. These models provide unique opportunities to study early events in peripheral nerve tumorigenesis. In this application we propose to use cell culture systems to test when in development EGFR expression generates a tumorigenic cell, and to characterize a human EGFR-expressing Schwann cell within neurofibromas. Finally, we will define cellular changes secondary to EGFR expression in the new transgenic model, focusing on the effects of mast cell recruitment. Together, these studies will identify cellular and molecular underpinnings of tumor formation in the nervous system, and identify therapeutic targets for the treatment of NF1. [unreadable] [unreadable] [unreadable]