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

Boato, Francesco, de la Cruz Thea, Benjamin, George, Shanu, Yang, Yu-Ting, Wang, Chia-Lin, Nahlé, Sarah, Janas, Justyna A, Coté, Jean-François, Van Aelst, Linda (October 2026) Distinct domains of Oligophrenin-1 regulate successive phases of cortical radial migration via RHOA- and PACSIN2-dependent mechanisms. Genes & Development. ISSN 0890-9369

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URL: https://www.ncbi.nlm.nih.gov/pubmed/42957276

DOI: 10.1101/gad.354125.126

Abstract

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.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions
CSHL Authors:	Wang, Chia-Lin Van Aelst, Linda Boato, Francesco de la Cruz Thea, Benjamin George, Shanu Yang, Yu-Ting
Communities:	CSHL labs > Van Aelst lab CSHL Post Doctoral Fellows
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	29 October 2026
Date Deposited:	02 Nov 2026 16:35
Last Modified:	02 Nov 2026 16:35
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42353

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