Transcriptional mechanisms of the neoteny of human cortical neurons

The human brain is characterized by its unique features, but the underlying developmental origins remain largely unknown. One important mechanism could be the unusually protracted rates of maturation of human cortical neurons, leading to neoteny of specific neuronal populations in the human cortex, compared with nonhuman primates (NHP). Very little is known about human neuronal neoteny, but interestingly it is also observed in human cortical neurons differentiated in vitro from pluripotent stem cells (PSC), even following their transplantation into the mouse developing brain, suggesting that intrinsic mechanisms are at stake. Here I will explore the transcriptional mechanisms controlling the rate of neuronal maturation in human neurons. I will focus on 2 different type of genes: the family of MEF2 transcription factors, which present a delayed increase in their expression in the human cortex compared with NHP, and the chromatin remodeling factors SMARCA2, SMARCA4 and CHD2, which present a delayed decrease of their expression in the human cortex. I will either perform gain (for MEF2s genes) or loss (for SMARCA2, SMARCA4 and CHD2) of function of these genes during in vitro corticogenesis from human PSC and following transplantation of human neurons in the mouse brain, followed by characterization of morphology and function of their synapses. Finally, depending on the results obtained I will investigate the mechanisms of action of the genes of interest in human cortical neurons