Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex

During evolution, the neocortex has expanded dramatically and folded in certain species, providing superior sensorimotor and cognitive abilities. Expansion of neural progenitors called bRGs and IPCs plays key roles in expansion and folding of the neocortex. Using mouse models, comparative genomics and human cerebral organoids, this study shows that Shh signaling expands bRG and IPC populations, leading to neocortical expansion and folding. The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basal radial glia (bRGs) and intermediate progenitor cells (IPCs). We found that constitutively active Sonic hedgehog (Shh) signaling expanded bRGs and IPCs and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of bRGs and IPCs and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but Shh signaling was not strongly active in the mouse embryonic neocortex, and blocking SHH signaling in human cerebral organoids decreased the number of bRGs. Mechanistically, Shh signaling increased the initial generation and self-renewal of bRGs and IPC proliferation in mice and the initial generation of bRGs in human cerebral organoids. Thus, robust SHH signaling in the human fetal neocortex may contribute to bRG and IPC expansion and neocortical growth and folding.