Zhang, Z.; Xu, Z.; Fu, T.; Li, J.; Yang, F.; Yang, C.; Zheng, W.; Sha, Z.; Gao, Y.; Sun, M.; Li, Z.; Ding, J.; LI, X.; Yang, Z.

The cerebral cortex, the anatomical foundation of human intelligence, underpins our advanced cognition and language. Deciphering the regulatory mechanisms driving its expansion in neuronal number and surface area is essential for elucidating the unique features of the human brain. Here, we demonstrate that ERK and PKA signaling pathways coordinately maintain the neurogenic identity and lineage specification of cortical radial glia (RGs) by suppressing gliogenic YAP and SHH signaling. Conversely, YAP signaling promotes the RG-ependymal glial cell lineage by inhibiting ERK, PKA, and SHH signaling, while SHH signaling facilitates the generation of cortical tripotential intermediate progenitor cells (Tri-IPCs) from RGs by repressing ERK, PKA, and YAP signaling. Cortical Tri-IPCs exhibit a sequential differentiation potential, giving rise to cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons. Importantly, we provide compelling evidence for the evolutionary conservation of these molecular mechanisms between mice and humans. Thus, ERK and PKA signaling in cortical RGs establish a mutually reinforcing positive feedback loop, mediated through repressing gliogenic YAP and SHH signaling, which collectively promote RG proliferation, protect neurogenesis, and drive human cortical expansion. This study identifies a unifying principle governing cortical neurogenesis, gliogenesis, expansion, and evolution.