Sonic hedgehog signaling: A conserved mechanism for the expansion of outer radial glia and intermediate progenitor cells and for the growth and folding of the neocortex.

The expansion of outer radial glia (oRGs, also called basal RGs) and intermediate progenitor cells (IPCs) has played a key role in the evolutionary expansion and folding of the neocortex, resulting in superior sensorimotor and cognitive abilities. In particular, oRGs, which are critical for both the increased production and lateral dispersion of neurons, are rare in lisencephalic species but vastly expanded in gyrencephalic species. However, the mechanisms that expand oRGs and IPCs are not well understood. We recently identified Sonic hedgehog (Shh) signaling as the first known signaling pathway necessary and sufficient to expand both oRGs and IPCs. Elevated Shh signaling in the embryonic neocortex leads to neocortical expansion and folding with normal cytoarchitecture in otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreases oRGs, IPCs, and neocortical size. We also showed that SHH signaling activity in fetal neocortex is stronger in humans than in mice and that blocking SHH signaling decreases oRGs in human cerebral organoids. Shh signaling may be a conserved mechanism that promotes oRG and IPC expansion, driving neocortical growth and folding in humans and other species. Understanding the mechanisms underlying species-specific differences in Shh signaling activity and how Shh signaling expands oRGs and IPCs will provide insights into the mechanisms of neocortical development and evolution.