Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma

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DESCRIPTION (provided by applicant): Medulloblastomas are the most common solid pediatric malignant tumors. These tumors arise in young children from dividing progenitor cells in the cerebellum, a brain region which develops after birth. The current treatments for medulloblastoma surgery, cranio-spinal radiation, and chemotherapy leave survivors with life-long, devastating side effects, including movement and cognitive disorders, seizures, psychiatric problems, and risk of other tumors due to radiation. These effects can be attributed to the inability of the treatments to preferentially target the tumor cells and spare the rest of the brain. Development of new medulloblastoma therapies that are more tumor-cell specific has been hampered by a lack of understanding of the molecular events causing the tumors and the cell biological events that promote their initiation and growth. Greater insight into how genes and proteins regulate proliferation in cerebellar progenitor cells, and how their dys-regulation contributes to tumorigenesis, will identify targets for new therapies that can specifically affect tumor growth without damaging the still-developing brain. Signal transduction pathways that regulate cerebellar progenitor cell division have been associated with medulloblastomas in humans and in mouse models. The pathways activated by the secreted ligands Sonic hedgehog (Shh) and insulin-like growth factor (IGF) are particularly important for cerebellar progentior cell proliferation, and their activity is increased in medulloblastomas. Primary cultures of proliferating mouse cerebellar progenitor cells have genetic profiles similar to those of human medulloblastomas, and they depend on Shh and IGF signaling for proliferation. In culture, these cells divide and differentiate much as they do in vivo, indicating that they are useful for studying how signaling pathways regulate proliferation during normal brain development and in medulloblastomas. The studies described in the proposal "Sonic hedgehog:Insulin-like growth factor cooperation in proliferating neural precursors" focus on characterizing how these pathways converge on a common target, insulin receptor substrate 1 (IRS1), to ultimately regulate translation of mRNAs into protein, an essential process for cell cycle progression during development and in cancer. These studies use primary cerebellar progenitor cultures and analysis of wild-type and IRS1-null mice to investigate how Shh regulates IRS1, how IRS1 functions in the developing cerebellum, and how the mRNA translation pathway component eIF4E, a downstream effector of IRS1, regulates new protein synthesis in cerebellar progenitors. The long- term goal of these studies is to determine how modulating the function of Shh and IGF downstream effectors such as IRS1 and eIF4E might be a useful therapeutic approach to treat medulloblastomas and other cancers where these pathways are operative, such as skin, prostate, and adult brain tumors.Medulloblastomas, the most common solid pediatric tumor, arise in the developing brain of young children. These tumors are currently treated with surgery radiation, and chemotherapy. Survivors suffer devastating life-long side effects due to the damage these treatments do to the still-developing brain. The studies proposed in 'Sonic hedgehog:Insulin-like growth factor cooperation in proliferating neural precursors' will shed light on how molecules that regulate cell division in immature neurons contribute to medulloblastoma formation and growth, and whether those molecules are potential targets for future treatments that will be less harmful to patients.