Identification of species differences in structure and function of COMMD3-BMI1 loci in neural stem cells

Human cerebral development is supported by the continuous proliferation of neural stem cells (NSCs), a process that morphologically and functionally distinguishes humans from other mammals. Several human brain-specific genes are known to contribute to the formation of such species differences. We hypothesize that differences at the epigenomic level also play a role in shaping species-dependent NSC behaviors. In this study, we examined structural interspecies differences in the components of protein regulator of cytokinesis 1 (PRC1), an important transcriptional repressor complex that functions in cortical development. We found that, for BMI1, diversity emerged in the fusion with COMMD3, generating three COMMD3-BMI1 transcripts (COMMD3-BMI1_1-3). We performed a series of knockdown experiments using AF22 cells, a human iPS cell-derived neural stem cell line, and found that the human-specific isoform, COMMD3-BMI1_3, showed the highest NSC proliferative activity, that was comparable to BMI1. These results suggest that the evolutionary acquisition of the human-specific COMMD3-BMI1 isoform has constituted species differences in cerebral development through the enhancement of NSC proliferative activity.