Regulation of stem cell differentiation during cerebellar development and medulloblastoma (2016–2017)
The regulation of cellular proliferation and differentiation is critical during both development and disease. For instance, controlling the balance between the proliferation of neural progenitor cells and their subsequent differentiation into neurons during development is central to the formation of the brain. Moreover, when proliferative cells fail to differentiate correctly, brain cancers can arise. Preliminary data reveal that the transcription factor Nfix plays a pivotal role in driving neural stem cell differentiation during development of the cerebellum, and its misregulation is implicated in the formation of medulloblastoma, a childhood cancer of the cerebellum that is the most frequent malignancy seen in paediatric patients. However, the processes underlying Nfix-mediated control of neural stem cell differentiation remains unclear. In this proposal we aim to understand the cellular and molecular mechanisms by which Nfix promotes neural stem cell differentiation during cerebellar development using knockout mouse lines and molecular approaches including transcriptomic sequencing and in vivo electoporation. Furthermore, we will elucidate how Nfix misregulation culminates in tumor formation using mouse models of medulloblastoma and over expression of NFIX within medulloblastoma cell lines. Collectively, this research will expand our understanding of neural stem cell biology within the developing brain, and will also provide crucal insights into the causes underpinning medulloblastoma.