PIEZO1-dependent mode switch of neuronal migration in heterogeneous microenvironments in the developing brain

The migration of newborn neurons is essential for brain morphogenesis and circuit formation, yet controversy exists regarding how neurons generate the driving force against strong mechanical stresses in crowded neural tissues. We found that cerebellar granule neurons employ a mechanosensing mechanism to switch the driving forces to maneuver in irregular brain tissue. In two-dimensional (2D) cultures, actomyosin is enriched in the leading process, exerting traction force on the cell soma. In tissue or 3D confinement, however, actomyosin concentrates at the posterior cell membrane, generating contractile forces that assist passage through narrow spaces, working alongside the traction force in the leading process. The 3D migration is initiated by the activation of a mechanosensitive channel, PIEZO1. PIEZO1-induced calcium influx in the soma triggers the PKC-ezrin cascade, which recruits actomyosin and transmits its contractile force to the posterior plasma membrane. Thus, migrating neurons adapt their motility modes in distinct extracellular environments in the developing brain.