Regulation of Cerebellum Growth and Development

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DESCRIPTION (provided by applicant): The normal growth of the cerebellum requires mitogenic signals and feedback mechanisms that limit cell division to the proper times and places. We will investigate mechanisms that control normal cerebellum growth and that fail during cerebellar tumorigenesis. Two growth zones contribute to cerebellar development: the ventricular zone where Purkinje and other cells form, and the external germinal layer that gives rise to granule cells, the most abundant type of neuron in the brain. We have shown that Sonic hedgehog (Shh) signaling protein, produced by Purkinje cells, is a powerful mitogen for cerebellar granule cell precursors. The Patched 1 transmembrane protein, produced in granule cell precursors, is a receptor for Shh. Shh activates the transcription of target genes by preventing Patched1 from inhibiting their transcription. We have shown that reduced human PATCHED1 function is associated with sporadic and inherited types of medulloblastoma. Medulloblastoma is the most common type of childhood malignant brain tumor, and it has an approximately 50 percent mortality rate. We have made a mouse model of medulloblastoma based on the human genetics of the disease, with reduced patched1 function leading to frequent tumors. The tumor cells are marked by lacZ expression, so they can be recognized long before an overt tumor forms. This allows investigation of early stages of tumorigenesis. We propose experiments to learn how Shh signaling controls normal granule cell development by affecting cell cycle and other regulators, and how reduced Patched 1 function leads to medulloblastoma. The specific aims are: 1. To investigate Shh regulation of the cell cycle and cell differentiation in cerebellar granule cell precursors. 2. To investigate how granule cell precursors stop responding to mitogenic effects of Shh and begin differentiation and migration. 3. To use mouse models of medulloblastoma to investigate mechanisms of tumorigenesis.