Metabolic Regulation of Neocortical Expansion in Development and Evolution

The neocortex, the seat of our higher cognitive abilities, has expanded in size during the evolution of certain mammals such as primates, including humans. This expansion occurs during development and is linked to the proliferative capacity of neural stem and progenitor cells (NPCs) in the neocortex. A number of cellintrinsic and cell-extrinsic factors have been implicated in increasing NPC proliferative capacity. However, NPC metabolism has only recently emerged as major regulator of NPC proliferation. In this Perspective, we summarize recent insights into the role of NPC metabolism in neocortical development and neurodevelopmental disorders and its relevance for neocortex evolution. We discuss certain human-specific genes and microcephaly-implicated genes that operate in, or at, the mitochondria of NPCs and stimulate their proliferation by promoting glutaminolysis. We also discuss other metabolic pathways and develop a perspective on how metabolism mechanistically regulates NPC proliferation in neocortical development and how this contributed to neocortex evolution.

Automated summary

The neocortex has expanded in certain mammals such as primates, including humans, and NPC metabolism is now recognized as a major regulator of NPC proliferation in neocortical development. Insights into the role of NPC metabolism in neurodevelopmental disorders and its relevance for neocortex evolution have been summarized, highlighting the impact of metabolism on NPC proliferation and neocortical development.