Epigenetic and metabolic regulation of developmental timing in neocortex evolution

The human brain is characterized by impressive cognitive abilities. The neocortex is the seat of higher cognition, and neocortex expansion is a hallmark of human evolution. While developmental programs are similar in different species, the timing of developmental transitions and the capacity of neural progenitor cells (NPCs) to proliferate differ, contributing to the increased production of neurons during human cortical development. Here, we review the epigenetic regulation of developmental transitions during corticogenesis, focusing mostly on humans while building on knowledge from studies in mice. We discuss metabolic-epigenetic interplay as a potential mechanism to integrate extracellular signals into neural chromatin. Moreover, we synthesize current understanding of how epigenetic and metabolic deregulation can cause neurodevelopmental disorders. Finally, we outline how developmental timing can be investigated using brain organoid models.