Distinct domains of Oligophrenin-1 regulate successive phases of cortical radial migration via RHOA- and PACSIN2-dependent mechanisms

Proper assembly of cortical circuits depends on the orderly migration of excitatory projection neurons, a multistep process marked by dynamic cell shape remodeling, including the transition from multipolar-to-bipolar morphology (MP-to-BP) followed by radial glial-guided locomotion. Although molecular players regulating individual stages have been identified, how these steps are coordinated remains unclear. Here, we uncover a critical role for the multidomain Rho-GAP oligophrenin-1 (OPHN1), an X-linked intellectual disability protein, as a dual-function regulator of radial migration. Using a molecular replacement strategy combined with live-cell imaging, we show that OPHN1 governs successive phases of migration through distinct domains and mechanisms: its GAP domain promotes the MP-to-BP transition by suppressing RHOA–ROCK signaling, whereas its second proline-rich domain regulates leading process remodeling and nucleokinesis during locomotion via interaction with the protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). Together, these findings reveal a previously unrecognized role for OPHN1 in early cortical development and demonstrate that its domain-specific functions facilitate stepwise control of radial migration during corticogenesis.