Human-Specific Genes and Neocortex Expansion in Development and Evolution

The expansion of the human neocortex, which constitutes a basis for our cognitive abilities, is due to an increased abundance and proliferative capacity of neural stem and progenitor cells (NPCs) during fetal cortical development. Specifically, NPCs in a secondary germinal zone called the subventricular zone, referred to as basal progenitors (BPs), are thought to be key for neocortex expansion. Here, a particularly important role has been attributed to one specific BP type called basal (or outer) radial glia (bRG).

In search for human-specific genome changes underlying neocortex expansion, we have found that the human-specific gene ARHGAP11B is specifically expressed in bRG and the NPCs from which bRG are derived. When expressed in embryonic mouse neocortex, ARHGAP11B causes amplification of BPs and is able to induce folding of the embryonic mouse neocortex, which is normally smooth. The ability of ARHGAP11B to amplify BPs is based on a single C-to-G base substitution that, due to a reading-frame shift resulting from altered mRNA splicing, is ultimately responsible for the appearance of a novel, human-specific 47-amino acid sequence in ARHGAP11B that is thought to be essential for BP amplification.