Proliferation of cerebellar neural progenitors and Shh-driven medulloblastoma requires suppression of WNT by GSK-3

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Project Summary During postnatal cerebellar neurogenesis, cerebellar granule neuron progenitors (CGNPs) proliferate to produce to the largest population of neurons in the brain. Impaired regulation CGNPs can give rise to severe neurodevelopmental disorders, including medulloblastoma and cerebellar hypoplasia. Although Sonic Hedgehog (SHH) signaling is known to positively regulate CGNP proliferation, the mechanisms that negatively regulate this proliferation are poorly understood. Recently I discovered that loss of GSK-3 function in CGNPs results in severe cerebellar hypoplasia due to decreased proliferation. I also found that disruption of GSK-3 in SHH-driven medulloblastoma inhibited tumor growth. These findings have uncovered a previously unrecognized mechanism regulating CGNPs and medulloblastoma cells through GSK-3. This proposal is focused on identifying the molecular mechanisms of GSK-3 regulation in the cerebellum and determining whether medulloblastoma, a neural-progenitor-derived cerebellar tumor, may share the requirement of CGNPs for GSK-3. In the proposal, I will use (i) pharmacological manipulation, (ii) conditional genetic models, (iii) cell cycle analysis and flow cytometry, and (iv) transcriptomic analysis to identify the mechanism of GSK-3 function in cerebellar and medulloblastoma tumor growth. I expect the results to show how GSK-3 contributes to physiological cerebellar growth and to show whether GSK-3 may be a promising target for medulloblastoma therapy. These studies will identify novel mechanisms regulating developmental and malignant growth in the cerebellum, with broad potential for translational impact. By completing this proposed research, I will gain critical training and experience in the investigation of growth regulation in both the developing brain and in brain tumors, while learning technical skills, ethical research conduct, and scientific communication.