Olson, James

Medulloblastoma, the most common malignant brain tumor in children, occurs in the developing cerebellum. Unlike other areas of the brain, cerebellar granular neurons undergo massive proliferation, migration, and differentiation in the early postnatal period. As cerebellar granular neuron precursors proliferate, multiple pathways collaborate to prevent premature neuronal differentiation (e.g., notch, REST) and drive proliferation (e.g., sonic hedgehog, Wnt, Nmyc). In normal development, these pathways eventually yield to those involved in differentiation and cell cycle arrest (e.g., neuroD2, neuroD, p27). Our studies, and those of other laboratories, show that pathways that drive proliferation and prevent differentiation in developing cerebellum are aberrantly active in medulloblastoma and that neuronal differentiation pathways are impaired. We focus on strategies for manipulating neurodevelopmental pathways for therapeutic purposes in medulloblastoma.