Many of the extraordinary intellectual capabilities of humans are attributed to the proper development and function of the neocortex. This region of the brain is responsible for higher cognitive functions such as sensory perception, spatial reasoning, and conscious thought, and is distinguished in humans by its large size and extensively folded pattern. However, the developmental events that underlie this structure have mostly been inferred from characterizations of the mouse or rat, whose neocortex is small and not folded.

Here, we directly characterize the progenitor cells present in the developing human neocortex. We find that the developing human neocortex utilizes a proliferative cell population that forms the outer subventricular zone (OSVZ), a region removed from the cerebral ventricles that is not present in the mouse. We further identify an OSVZ progenitor cell type known as an outer radial glial (oRG) cell and demonstrate using real-time imaging that they undergo self-renewing asymmetric divisions to generate neuronal progenitor cells. oRG cells function as neural stem cells and underlie an OSVZ lineage of progenitor cells, which over the course of many cell cycles amplifies neuron number and likely modifies the trajectory of migrating neurons.

Because the establishment of non-ventricular radial glia may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain, we further discuss the prevalence of oRG cells and OSVZ proliferation in different species throughout evolution. We learn that OSVZ proliferation is present in all superorders of placental mammals, but only in those species with folded brains are these mechanisms appreciably utilized. To gain insight into the molecular and evolutionary bases for these phenotypic differences, we performed serial microrarray analysis to uncover gene co-expression patterns present in the developing human neocortex. From these data, we identified co-expression modules that correspond to human radial glia and further determined genes within these modules that have undergone human-specific evolutionary changes. This data serves as a molecular substrate for comparisons of radial glia between species and will help elucidate the molecular mechanisms that drive OSVZ proliferation.