Integrated ERK‐PKA‐YAP/TAZ‐SHH Signaling Orchestrates Cortical Radial Glia Identity and Lineage Diversification

Abstract The signaling pathways governing cortical neurogenesis and gliogenesis in mice are well‐defined, yet how they integrate to control the lineage progression of cortical radial glia (RGs) remains incompletely understood. Here, using mouse genetic models, it is demonstrated that ERK and PKA signaling cooperate to preserve the neurogenic capacity of cortical RGs by suppressing the gliogenic pathways YAP/TAZ and SHH. Specifically, YAP/TAZ signaling drives cortical RGs toward an ependymal fate, while SHH signaling promotes the generation of tripotential intermediate progenitor cells that produce cortical astrocytes and oligodendrocytes, and olfactory bulb interneurons. Reanalysis of published human cortical scRNA‐seq data further revealed that the functional roles of these signaling pathways are conserved between mouse and human cortical RGs. Furthermore, human cortical outer RGs acquire dominant ERK/PKA signaling through a self‐reinforcing loop that suppresses both YAP and SHH signaling, markedly enhancing self‐renewal and extending neurogenesis. Thus, a tripartite network of ERK/PKA, YAP/TAZ, and SHH whose cross‐repressive logic coordinates neurogenesis with gliogenesis and may underlie evolutionary expansion, providing a framework for understanding cortical development and evolution, is identified.