Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex

The human neocortex is increased in size and complexity as compared to most other species. Neocortical expansion has recently been attributed to protracted neurogenesis by outer radial glial (oRG) cells in the outer subventricular zone (oSVZ), a region present in humans but not in rodents. The mechanisms of human oRG cell generation are unknown, but are proposed to involve division of ventricular radial glial (vRG) cells; neural stem cells present in all developing mammals. Here we show that human vRG cells produce oRG cells and seed formation of the oSVZ via horizontal divisions, which occur more frequently in humans than in rodents. We further find that oRG cell mitotic behavior is cell intrinsic, and that the basal fiber, inherited by oRG cells after vRG division, determines cleavage angle. Our results suggest that altered regulation of mitotic spindle orientation increased oRG cell numbers, and ultimately neuronal numbers, during human brain evolution.