PhD Candidate McGill University Toronto, Ontario, Canada
Abstract: Forkhead box G1 (FOXG1) is a crucial transcription factor for neural stem cell (NSC) proliferation during cortical expansion. As NSCs transition from proliferation to differentiation, FOXG1 levels decrease, coinciding with a metabolic shift from glycolysis to oxidative phosphorylation. This metabolic reprogramming is increasingly recognized as a driver of differentiation. Moreover, evidence suggests that FOXG1 may localize to mitochondria and influence bioenergetic state of NSCs. Given the intricate relationship between proliferation, differentiation, and metabolic state, we aim to investigate the potential link between metabolic state and FOXG1 stability. To accomplish this, we first determined a baseline stability of FOXG1 in two cell types: a HEK293 testing model, and three iPSC-derived cortical NSC lines. We then perturbed various metabolic pathways in a pharmacological screen in HEK293 cells, before validating in iPSC-derived NSCs. We identified several promising candidates during the initial screening, many with >2-fold change on FOXG1 levels. However, these effects were not consistently seen in all three of our NSC models. These results suggest FOXG1 may be regulated by metabolic state of the cell, but that the proper coordination of this would be highly complex and require very specific intracellular conditions. To characterize these conditions, we will be conducting a systematic analysis of metabolic activity within our NSC cell lines during proliferation and during the onset of differentiation to inform what metabolic changes best promote loss of FOXG1 and neuronal differentiation. This research would establish a mechanistic link for the onset of differentiation in cortical NSCs and be the first to potentially identify FOXG1 as a master metabolic regulator of this event.
