This application is from a collaborative research team, which proposes to develop, characterize, and validate new mouse models of NF2-associated meningioma development with the goal of facilitating the translation of basic research data into new treatments that will benefit individuals with NF2-related and sporadic meningioma. Meningioma, a brain tumor that arises from the cells that form a protective covering over the brain (leptomeningeal cells), is the second most common tumor in individuals affected with neurofibromatosis 2 (NF2). Although typically regarded as ¿benign¿ tumors, meningiomas can behave in a clinically aggressive fashion, invade brain tissue, recur after resection, and spread along the leptomeninges to involve multiple regions. Studies from a number of laboratories have shown that inactivation of the NF2 gene is associated with meningioma formation in all NF2-associated and 60' of sporadic meningiomas. Our initial attempts to develop a mouse model for NF2-associated meningiomas were successful. Meningiomas form in 40' of these mice and are not clinically apparent until late in life. Recent studies from our laboratory have demonstrated that loss of another NF2-related tumor suppressor, Protein 4.1B, is observed in 60' of NF2-associated and sporadic meningiomas. We have shown that both the NF2 gene products, merlin, and Protein 4.1B function as growth regulators for meningiomas in tissue culture model systems and that combined loss of both merlin and Protein 4.1B is seen more frequently in high-grade meningiomas. The generation and characterization of a preclinical mouse model for meningiomas through targeted disruption of the Protein 4.1B and Nf2 genes could facilitate the assessment of potential targeted therapies for this common brain tumor in NF2.