The ability of radial glial progenitors (RGPs) to generate cortical neurons is determined by local extracellular factors and signaling pathways intrinsic to RGPs. Here we find that GPR157, an orphan G protein-coupled receptor, localizes to RGPs' primary cilia exposed to the cerebrospinal fluid (CSF). GPR157 couples with Gq-class of the heterotrimeric G-proteins and signals through IP3-mediated Ca(2+) cascade. Activation of GPR157-Gq signaling enhances neuronal differentiation of RGPs whereas interfering with GPR157-Gq-IP3 cascade in RGPs suppresses neurogenesis. We also detect the presence of putative ligand(s) for GPR157 in the CSF, and demonstrate the increased ability of the CSF to activate GPR157 at neurogenic phase. Thus, GPR157-Gq signaling at the primary cilia of RGPs is activated by the CSF and contributes to neurogenesis.