Human-specific ARHGAP11B ensures human-like basal progenitor levels in hominid cerebral organoids.

The human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of ARHGAP11B's contribution to this expansion during hominid evolution is unknown. Here we address this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. ARHGAP11B expression in chimpanzee cerebral organoids doubles basal progenitor levels, the class of cortical progenitors with a key role in neocortex expansion. Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level. Moreover, ARHGAP11A or ARHGAP11B rescue experiments in ARHGAP11A plus ARHGAP11B double-knockout human forebrain organoids indicate that lack of ARHGAP11B, but not of ARHGAP11A, decreases the abundance of basal radial glia-the basal progenitor type thought to be of particular relevance for neocortex expansion. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to ensure the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.

Evolution of genetic mechanisms regulating cortical neurogenesis.

The size of the cerebral cortex increases dramatically across amniotes, from reptiles to great apes. This is primarily due to different numbers of neurons and glial cells produced during embryonic development. The evolutionary expansion of cortical neurogenesis was linked to changes in neural stem and progenitor cells, which acquired increased capacity of self-amplification and neuron production. Evolution works via changes in the genome, and recent studies have identified a small number of new genes that emerged in the recent human and primate lineages, promoting cortical progenitor proliferation and increased neurogenesis. However, most of the mammalian genome corresponds to noncoding DNA that contains gene-regulatory elements, and recent evidence precisely points at changes in expression levels of conserved genes as key in the evolution of cortical neurogenesis. Here, we provide an overview of basic cellular mechanisms involved in cortical neurogenesis across amniotes, and discuss recent progress on genetic mechanisms that may have changed during evolution, including gene expression regulation, leading to the expansion of the cerebral cortex.