Human‐biased TMEM25 expression promotes expansion of neural progenitor cells to alter cortical structure in the developing brain

Cortical expansion has occurred during human brain evolution. By comparing human and mouse RNA‐seq datasets, we found that transmembrane protein 25 (TMEM25) was much more highly expressed in human neural progenitors (NPCs). Overexpression of either human TMEM25 or mouse Tmem25 similarly promoted mouse NPC proliferation in vitro. Mimicking human‐type expression of TMEM25 in mouse ventricular cortical progenitors accelerated proliferation of basal radial glia (bRG) and increased the number of upper‐layer neurons in vivo. By contrast, RNA‐seq analysis, and pharmacological assays showed that knockdown of TMEM25 in cultured human NPCs compromised the effects of extracellular signals, leading to cell cycle inhibition via Akt repression. Thus, TMEM25 can receive extracellular signals to expand bRG in human cortical development. A high level of transmembrane protein 25 expression in human neural progenitors promotes expression of the cell cycle regulatory genes CDK1 and CCNB1 through activating Akt phosphorylation. This process promotes generation of basal radial glia to increase the density of upper‐layer neurons in human cortical development.