Abstract
The neocortex is the site of higher order cognitive functioning and sensory processing. It is an essential region of the brain as a reduction in neocortical mass at birth due to reduced neuronal number is often associated with intellectual deficits and behavioural abnormalities. It is thus important that we decipher how neurogenesis is regulated during neocortical development. My research has focused on determining how neocortical progenitors decide to proliferate or differentiate; a cell fate choice that dictates how many neurons are born during development. Specifically, I have studied the basic helix-loop-helix transcription factors encoded by the proneural genes Neurogenin 2 (Neurog2) and Achaete scute-like 1 (Ascl1). Neurog2 and Ascl1 are expressed in neural progenitor cells and give rise to distinct neuronal and glial cell types. In the developing telencephalon, Neurog2 promotes the differentiation of excitatory projection neurons while Ascl1 promotes the differentiation of interneurons and glioblasts. My general hypothesis was that Neurog2-Ascl1 form a genetic switch, and that the extrinsic/intrinsic cues that control this genetic switch lie at the crux of cortical progenitor cell fate decisions, ensuring that cortical cells differentiate in sequence and on time. Data that supports this hypothesis, demonstrates that Neurog2-Ascl1 do indeed form a cross-repressive genetic switch, acting together to regulate the timing of laminar fate transitions, and conferring a metastable stem cell state onto a subpool of cortical progenitors. Furthermore, I made inroads into understanding how Neurog2 proneural activity is regulated, demonstrating that Mbt1, a polycomb group protein, regulates Neurog2 function. In sum, through my PhD work, I have made significant inroads into deciphering the molecular mechanisms that control the balance between neocortical progenitor cell self-renewal and differentiation.
