Arhgef1 Deletion Disrupts Early Cortical Neurogenesis via PAK1 Overactivation and Causes Motor Dysfunction in Adulthood
7 affiliations
- 1State Key Laboratory of Bioactive Molecules and Druggability Assessment Guangdong Basic Research Center of Excelence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University Guangzhou China
- 2JNU‐HKUST Joint Laboratory for Neuroscience and Innovative Drug Research Guangdong Hong Kong‐Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research Jinan University Guangzhou China
- 3Department of Pharmacy Zhujiang Hospital Southern Medical University Guangzhou China
- 4Department of Pharmacy School of Medicine the Sixth Affiliated Hospital of South China University of Technology (Nanhai District People's Hospital of Foshan) Foshan China
- 5Guangdong‐Hong Kong‐Macau Institute of CNS Regeneration Key Laboratory of CNS Regeneration (Ministry of Education) Jinan University Guangzhou China
- 6School of Biomedical Sciences and Gerald Choa Neuroscience Institute The Chinese University of Hong Kong Hong Kong China
- 7Neurological Research Institute of Integrated Traditional Chinese and Western Medicine First School of Clinical Medicine The First Affiliated Hospital Guangdong Pharmaceutical University Guangzhou China
Abstract
Precise regulation of early cortical development is essential for the establishment of normal brain function, and its disruption can contribute to the pathogenesis of neurodevelopmental disorders (NDDs). Impaired motor function is a prominent early manifestation of various NDDs, yet the mechanisms remain elusive. Here, we identified ARHGEF1, a Rho family guanine nucleotide exchange factor highly expressed during early corticogenesis, as a novel regulator in embryonic cortical neurogenesis and adult motor function. By Emx1‐Cre‐mediated forebrain deletion of Arhgef1 in mice (Arhgef1 cKO mice), early cortical neurogenesis is specifically disrupted, leading to reduced deep‐layer cortical neurons. Mechanistically, Arhgef1 deficiency overactivates RAC1/CDC42‐PAK1‐Cofilin signaling in early cortical development, whereas pharmacological PAK1 inhibition within this critical window rescues the genesis of deep‐layer cortical neurons. Importantly, Arhgef1 cKO mice exhibit remarkable motor learning and coordination deficits in adulthood, accompanied by altered neuronal morphology in the motor cortex and impaired neuronal activities in motor circuits. In all, we elucidate a critical developmental window when ARHGEF1 governs corticogenesis via negatively regulates PAK1‐dependent pathway and further reveal an important role for ARHGEF1 in maintaining normal motor function in adulthood.
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BibTeX
@article{li2026arhgef1,
title = {{Arhgef1 Deletion Disrupts Early Cortical Neurogenesis via PAK1 Overactivation and Causes Motor Dysfunction in Adulthood}},
author = {Liuren Li and Xuanyue Ma and Zhenyu Ding and Bang Sun and Linglin Liu and Hei Matthew Yip and Wei Wang and Tianying Wu and Yuan Guo and Yinghui Peng and Shiqing Zhang and Jacque Pak Kan Ip and Li Zhang and Keshen Li and Lei Shi},
journal = {Advanced Science},
year = {2026},
month = oct,
doi = {10.1002/advs.78426},
url = {https://doi.org/10.1002/advs.78426},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Arhgef1 Deletion Disrupts Early Cortical Neurogenesis via PAK1 Overactivation and Causes Motor Dysfunction in Adulthood
AU - Liuren Li
AU - Xuanyue Ma
AU - Zhenyu Ding
AU - Bang Sun
AU - Linglin Liu
AU - Hei Matthew Yip
AU - Wei Wang
AU - Tianying Wu
AU - Yuan Guo
AU - Yinghui Peng
AU - Shiqing Zhang
AU - Jacque Pak Kan Ip
AU - Li Zhang
AU - Keshen Li
AU - Lei Shi
PY - 2026
DA - 2026/10/25
JO - Advanced Science
DO - 10.1002/advs.78426
UR - https://doi.org/10.1002/advs.78426
AB - Precise regulation of early cortical development is essential for the establishment of normal brain function, and its disruption can contribute to the pathogenesis of neurodevelopmental disorders (NDDs). Impaired motor function is a prominent early manifestation of various NDDs, yet the mechanisms remain elusive. Here, we identified ARHGEF1, a Rho family guanine nucleotide exchange factor highly expressed during early corticogenesis, as a novel regulator in embryonic cortical neurogenesis and adult motor function. By Emx1‐Cre‐mediated forebrain deletion of Arhgef1 in mice (Arhgef1 cKO mice), early cortical neurogenesis is specifically disrupted, leading to reduced deep‐layer cortical neurons. Mechanistically, Arhgef1 deficiency overactivates RAC1/CDC42‐PAK1‐Cofilin signaling in early cortical development, whereas pharmacological PAK1 inhibition within this critical window rescues the genesis of deep‐layer cortical neurons. Importantly, Arhgef1 cKO mice exhibit remarkable motor learning and coordination deficits in adulthood, accompanied by altered neuronal morphology in the motor cortex and impaired neuronal activities in motor circuits. In all, we elucidate a critical developmental window when ARHGEF1 governs corticogenesis via negatively regulates PAK1‐dependent pathway and further reveal an important role for ARHGEF1 in maintaining normal motor function in adulthood.
SN - 2198-3844
ER -