The role of ASCL1 and MYCN in human brain development

ended

The evolutionary expansion of the neocortex in the primate lineage, and particularly in humans, underpins our higher cognitive abilities. Neural stem and progenitor cells (NPCs) show increased duration of proliferative phases in humans when compared to other mammals and particularly mice. However, the mechanisms responsible for these evolutionary differences in progenitor properties are poorly understood. In this study, I aim to explore the function of the ASCL1 and MYCN proteins in human NPCs. These two factors are crucial to promote proliferation in different NPC populations of the mouse forebrain, but their function in promoting proliferation of human NPCs, where they are broadly expressed, is not known. I will evaluate the spatio-temporal expression of ASCL1 and MYCN throughout human neocortical development and I will assess their cellular functions during NPC expansion using loss-of-function experiments. Finally, I will determine if ASCL1 and/or MYCN regulation have diverged between mouse and human to allow for the extended proliferative capacity of human NPCs. For this project, I will use human embryonic and fetal brain tissue and pluripotent stem cell-derived 2D neuronal and 3D spheroid cultures as in vitro models that recapitulate many aspects of human brain development. Together, this work will provide insights into the mechanisms regulating the duration of NPC expansion, a crucial parameter that underscores key differences in brain size between species, and will help to better assess the pathological mechanisms at the origin of neurodevelopmental diseases.