Understanding Human Cortical Expansion Using Pluripotent Stem Cell-Derived Brain Organoids: Insights Into Progenitor...

The evolution of the human brain underlies our higher-order cognitive functions. In particular, the cerebral cortex, the outermost layer of the brain, has rapidly evolved to contain a disproportionately large number of neurons relative to the rest of the brain. Much of this expansion is attributed to the enlargement and diversification of the pool of neural precursors, which proliferate and differentiate into the neurons and glia of the brain. How the human cerebral cortex has evolved remains an active area of investigation. With the advent of pluripotent stem cell and brain organoid technologies, comparative genomic studies between humans, mice, and nonhuman primates have identified human-specific genes or pathways during neurodevelopment. The utility of these models relies on the ability of brain organoids to preserve the cytoarchitecture and species-specific developmental trajectories of diverse neural and glial cell types that are observed in vivo. This review will discuss how brain organoids recapitulate aspects of interspecies differences during cortical development, specifically neural precursor expansion, neurogenesis, and gliogenesis, and how these models can be improved to enable a deeper understanding of human brain evolution. Unraveling the cellular and molecular mechanisms underlying cross-species differences in brain expansion could also provide key insights into neurodevelopmental diseases, particularly those where brain size is affected.