Pediatric brain tumors are the most common solid tumors in children and are also the most common cause of cancer death in children. Gliomas account for ~85% of primary brain tumors in children. The most common gliomas in children include diffuse intrinsic pontine glioma (DIPG), atypical teratoid/rhabdoid tumor (AT/RT), pilocytic astrocytoma (PA), and glioblastoma (GBM). However, the etiology of these tumors is unknown. There is mounting evidence that early in life the brainstem has unique developmental and growth features. Importantly, these brainstem growth features are recapitulated during brain tumor development. In fact, the majority of DIPGs and other pediatric gliomas arise from the pons or midbrain. These data suggest that the postnatal brainstem growth pattern predisposes the brain to the formation of these tumors. This proposal will focus on the intrinsic regulation of cell growth and/or survival in DIPG, AT/RT, PA, and GBM. The central hypothesis of this proposal is that intrinsic regulatory mechanisms within tumor cells and/or the microenvironment in which they reside contribute to pediatric brain tumor development. We propose to address the following questions: 1) What molecular mechanisms define growth rate in pediatric brain tumors? 2) Does intrinsic (cell autonomous) or extrinsic (autocrine or paracrine) mechanisms of cell death regulate cell growth in pediatric brain tumors? 3) Is the cell of origin in DIPG gliomas defined and are extrinsic factors or the microenvironment a requirement for tumor formation? This study will provide novel information on the mechanisms that control the growth of these pediatric brain tumors. This knowledge may help target these tumors for therapy and may ultimately reduce the mortality rate of these devastating cancers.