Distinct domains of Oligophrenin-1 regulate successive phases of cortical radial migration via RhoA- and Pacsin2-dependent mechanisms
- 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA
- 2Montreal Clinical Research Institute (IRCM), Université de Montréal, Montréal, QC H2W 1R7, Canada
- 3Department of Pathology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
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.
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BibTeX
@misc{boato2026distinct,
title = {{Distinct domains of Oligophrenin-1 regulate successive phases of cortical radial migration via RhoA- and Pacsin2-dependent mechanisms}},
author = {Francesco Boato and Benjamin de la Cruz Thea and Shanu George and Yu-Ting Yang and Chia-Lin Wang and Sarah Nahlé and Justyna A. Janas and Jean-François Coté and Linda Van Aelst},
howpublished = {Genes \& development},
year = {2026},
month = oct,
doi = {10.1101/gad.354125.126},
url = {https://doi.org/10.1101/gad.354125.126},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Distinct domains of Oligophrenin-1 regulate successive phases of cortical radial migration via RhoA- and Pacsin2-dependent mechanisms
AU - Francesco Boato
AU - Benjamin de la Cruz Thea
AU - Shanu George
AU - Yu-Ting Yang
AU - Chia-Lin Wang
AU - Sarah Nahlé
AU - Justyna A. Janas
AU - Jean-François Coté
AU - Linda Van Aelst
PY - 2026
DA - 2026/10/29
PB - Genes & development
DO - 10.1101/gad.354125.126
UR - https://doi.org/10.1101/gad.354125.126
AB - 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.
SN - 0890-9369
SN - 1549-5477
ER -