Mechanisms of human neocortical expansion

One of the most remarkable features of human brain evolution is the enormous increase in neuron number and the transformation of the lissencephalic cortex into a highly folded gyrencephalic cortex. This expansion is established primarily by large numbers of a specific type of neural stem cell, the outer radial glial (oRG) cell, present in the developing human brain. The developmental origins of oRG cells, and the mechanisms regulating their proliferation, are unknown. Using time-lapse imaging of human fetal cortical slices, we find that oRG cells are progeny of ventricular radial glial (vRG) cells, the primary neural stem cell present in all mammals. Horizontal vRG divisions, which are far more common in human than in mouse, lead to oRG cell generation, while vertical divisions do not. These results suggest that an increase in horizontal vRG divisions might have expanded the oRG cell population during primate brain evolution. We next use dissociated human fetal cortical cultures to interrogate the molecular pathway controlling a unique oRG cell behavior called called mitotic somal translocation (MST). During MST, the oRG cell body rapidly translocates a distance of several cell diameters towards the cortical plate immediately prior to cytokinesis. We find that oRG cell MST and cleavage angle regulation are cell intrinsic, and that MST is independent of mitosis. Activation of the Rho effector ROCK and of non-muscle myosin II, but not microtubule polymerization or centrosomal guidance, is required for MST. Furthermore, oRG cell MST contributes to radial oSVZ expansion. Finally, we describe several genetic mutations that target the RhoA-ROCK-myosin II pathway and cause cortical malformations in humans, including microcephaly, periventricular heterotopia, and lissencephaly. Interestingly, many of these mutations produce very minimal phenotypes in mice. We propose that MST may be the primary target of these diseases, as oRG cells compose a very small proportion of neural progenitor cells in mice. Given our discovery of the origin of oRG cells and the molecular motor driving MST, the field will now be in a better position to understand the function of oRG cells and oRG-specific behaviors such as MST in human brain development and disease