The cerebral cortex is a major integrative centre of the human brain and implements critical functions including sensory processing, motor control, attention, higher cognition, and consciousness. The cortex has expanded during human evolution to contain approximately 16 billion neurons, the highest number of any terrestrial mammal. This is partly due to primate-specific and human-specific changes in the patterns of cortical progenitor proliferation and differentiation during development. The relative inaccessibility of human and primate cortical development has however hindered the study of the molecular mechanisms which underly it and are responsible for human cortical expansion.

The advent of pluripotent stem cell (PSC) derived models of human and non-human primate corticogenesis has revolutionised the study of human cortical development, enabling the characterisation of cell-autonomous developmental mechanisms, comparative studies with more closely related species, and experimental testing of hypotheses on gene function and regulation. In the work presented here, I firstly examine the pathways that specify the generation of cortical or neighbouring developmental fates in such an in vitro cortical model, finding them to be similar to those which pattern the developing brain.

Secondly, I use knockdown and overexpression experiments as well as newly obtained and published bulk and single-cell RNA-sequencing data from human and macaque cortical progenitors to investigate how gene expression levels regulate cell-autonomous differences in progenitor proliferation and developmental timing between the two species. Finally, I identify hundreds of genes which regulate human cortical progenitor output through a genome-wide CRISPR-knockout screen in an in vitro model of cortical development. Overall, this work advances our understanding of how PSC-derived models can be used to study human cortical development and their limitations, identifies genes which regulate human cortical progenitor proliferation and differentiation, and proposes testable hypotheses of the molecular mechanisms by which differential gene expression may contribute to the evolutionary expansion of the human cerebral cortex.