Neurofibromatosis 1 (NF1) is the most common genetic condition affecting the nervous system. In children with NF1, one of the most clinically devastating complications of neurofibromatosis 1 (NF1) is the development of gliomas (tumors composed of astrocytes or astroglial cells) of the optic nerve and chiasm. These tumors occur almost exclusively in children younger than 7 years of age. These tumors are classified as low-grade malignancies; however, they may continue to grow and result in blindness, early puberty, and other neurologic abnormalities. Despite significant advances in our understanding of the molecular biology of the NF1 gene product neurofibromin as a growth regulator for many other cell types important for the development of clinical symptoms in NF1, there is comparatively little known about the role of the NF1 gene in astrocytoma development. Our ability to design rational therapies for NF1-associated astrocytomas is dependent on an improved understanding of the mechanisms by which loss of neurofibromin expression and function promotes tumor formation and progression.

Previous work from our laboratory has demonstrated that reduced or absent neurofibromin expression in astrocytes is associated with increased RAS pathway activation and increased cell proliferation. We have demonstrated that the Nf1 protein neurofibromin controls not only cell growth, but also cell survival and cell motility. We have generated mice that lack neurofibromin expression in astrocytes. These mice have more growing astrocytes in their brains; however, they do not develop brain tumors. These observations suggest that other genetic and non-genetic factors play a role in the development of these devastating tumors in children with NF1.

In this proposal, we plan to test the hypothesis that NF1-associated astrocytoma formation requires (1) a permissive brain environment, (2) loss of Nf1 in the appropriate cell type, or (3) additional cooperating genetic changes. The experiments proposed are directed at determining the critical cellular and genetic parameters that facilitate NF1-associated astrocytoma formation by studying the effect of Nf1 loss on astroglial cell biology in vitro and in vivo as well as to apply recent insights derived from the study of human NF1-associated brain tumors to Nf1 astrocytoma mouse modeling. In addition, we propose to further characterize the biological properties of Nf1-deficient astroglial cells.

The results obtained from these studies will likely provide insights into how the NF1 gene controls the growth of astrocytes relevant to astrocytoma formation. These insights may identify specific targets for the design of therapies for NF1-associated brain tumors in children. In addition, the development of an accurate model of NF1-associated brain tumors will facilitate the preclinical evaluation of novel therapies. Lastly, the identification of additional genetic and non-genetic factors that promote brain tumor formation in NF1 will have considerable impact on future approaches to brain tumor treatment.