GPR161 mechanosensitivity at the primary cilium drives neuronal saltatory migration

The saltatory migration of neurons is essential for brain formation. Whether mechanical stimuli regulate this process is unknown. Here, we show that the primary cilium acts as a mechanical sensor through GPR161. Using an ex vivo neuronal migration model and microfluidic assays, we demonstrate that fluid shear stress induces migration via the mechanoreceptor GPR161 at the primary cilium, with its mechanosensitive helix 8 being essential. We demonstrate that GPR161 activates a recently discovered cAMP/PKA signaling pathway leading to the phosphorylation of NDE1, a dynein complex regulator, and microtubule organization to regulate migration. These findings unveil a critical role of mechanosensation in neuronal migration, regulating the rhythmicity of migration, in concert with the externalization/internalization dynamics of the primary cilium.