More than meets the eye: exploring Sonic Hedgehog medulloblastoma from a neurodevelopmental perspective

Cerebellar development is a complex process that requires tight orchestration of various factors to ensure proper cerebellar function. The relatively long time-span for the cerebellum to reach maturity makes the cerebellum vulnerable to developmental dysregulation, which can ultimately manifest in the malignant transformation into medulloblastoma, one of the most frequently diagnosed childhood brain tumors. This thesis aimed at addressing some of the complex interplay of the molecular players during cerebellar development and how they may facilitate tumor formation.In Chapter 1, the development of cerebellar granule cells, the most abundant cell type of the brain, is described based on current literaturereviewed in Chapter 1. The predecessorsir progenitors of these granule cells (e.g., cerebellar granule neuron progenitors or CGNPs) are known to be the cell-of-origin for at least two subtypes of medulloblastoma. In Chapter 2, we studied the dynamic changes in gene expression in murineouse CGNPs during brain development and shed light on the age-specific onset and pathway mutations that are associated with SHH medulloblastoma. In Chapter 3, we explored the role of transcription factor CREB in CGNP development and medulloblastoma therapy, since we had discovered that CREB phosphorylation activity status strongly correlates with patient survival in SHH and Group 3 medulloblastoma. In Chapter 4, we assessed the role contribution genes encoding histone modifier complexes, theof histone modifier KMT2D into medulloblastoma pathogenesis. In the last experimental chapter (Chapter 5), we set out to establish primary pediatric brain tumor cell cultures that faithfully maintain tumor characteristics, which can be employed as models for understanding tumor biology and therapeutic discovery. Finally, we summarized our findings and discussed their implications in Chapter 6