Neurofibromatosis 1 (NF1) is a comm mon autosomal dominant disorder in which affected individuals develop benign and malignant tumors. This application targets on of the most important clinical issues in NF1. Optic pathway gliomas (astrocytomas) are the second most common tumor in NF1, often leading to blindness and neurologic impairment. Despite significant advances in our understanding of the molecular biology of the NF1 gene, very little is known about these tumors or the role of the NF1 gene in regulating astrocyte growth. The NF1 gene was identified by positional cloning and its protein product, neurofibromin, was shown to function as a GTPase-activating protein (GAP) for p21-ras. Reduced expression of neurofibromin in some tumors results in increased p21-ras activity and cell proliferation. However, it is not known whether the NF1 gene is a growth regulator for astrocytes, whether it functions as a p21-ras regulator in astrocytes, and whether loss of NF1 expression is required for astrocytoma development. Previously, it was demonstrated that mice heterozygous for a targeted NF1 gene mutation have increased numbers of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in their brains. In addition, it was demonstrated that primary astrocytes from NF1 +/- mice proliferate faster in vitro that primary astrocytes derived from NF1 +/+ littermates. These results suggest that neurofibromin might function as a tumor suppressor protein for astrocytes, such that reduced or absent NF1 gene expression might result in increased astrocyte proliferation and tumor formation. In this application it is proposed to test the hypothesis that neurofibromin functions as a negative growth regulator of astrocytes in vitro and in vivo. Specifically, it is proposed to (1) determine the relationship between neurofibromin expression and p21-ras activity during normal astrocyte development and growth arrest, (2) determine whether decreased NF1 expression results in increased astrocyte proliferation, and (3) generate transgenic mice with a targeted disruption of the NF1 gene restricted to astrocytes.
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