iScience (Jun 2021)
Arhgef2 regulates neural differentiation in the cerebral cortex through mRNA m6A-methylation of Npdc1 and Cend1
- Pei Zhou,
- Yifei Qi,
- Xiang Fang,
- Miaomiao Yang,
- Shuxin Zheng,
- Caihua Liao,
- Fengying Qin,
- Lili Liu,
- Hong Li,
- Yan Li,
- Ethiraj Ravindran,
- Chuanbo Sun,
- Xinshu Wei,
- Wen Wang,
- Liang Fang,
- Dingding Han,
- Changgeng Peng,
- Wei Chen,
- Na Li,
- Angela M. Kaindl,
- Hao Hu
Affiliations
- Pei Zhou
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Yifei Qi
- Division of Uterine Vascular Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China; Corresponding author
- Xiang Fang
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Miaomiao Yang
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Shuxin Zheng
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Caihua Liao
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Fengying Qin
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Lili Liu
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Hong Li
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Yan Li
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Ethiraj Ravindran
- Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children, Berlin, Germany
- Chuanbo Sun
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Xinshu Wei
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China; School of Medicine, South China University of Technology, 510006 Guangzhou, China
- Wen Wang
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518005, China
- Liang Fang
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518005, China
- Dingding Han
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Changgeng Peng
- The First Rehabilitation Hospital of Shanghai, Tongji University School of Medicine, 200029 Shanghai, China
- Wei Chen
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518005, China
- Na Li
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China
- Angela M. Kaindl
- Charité - Universitätsmedizin Berlin, Institute of Cell Biology and Neurobiology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children, Berlin, Germany
- Hao Hu
- Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China; School of Medicine, South China University of Technology, 510006 Guangzhou, China; Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623 Guangzhou, China; Third Affiliated Hospital of Zhengzhou University, 450052 Zhengzhou, China; Corresponding author
- Journal volume & issue
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Vol. 24,
no. 6
p. 102645
Abstract
Summary: N6-methyladenosine (m6A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of Arhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m6A methylation. Arhgef2 knockout decreases expression of Mettl14 and total m6A level significantly in the cerebral cortex. m6A sequencing reveals that loss of Arhgef2 reduces m6A methylation of 1,622 mRNAs, including Npdc1 and Cend1, which are both strongly associated with cell cycle exit and terminal neural differentiation. Arhgef2 deficiency decreases m6A methylations of the Npdc1 and Cend1 mRNAs via down-regulation of Mettl14, and thereby inhibits the translation of Npdc1 and nuclear export of Cend1 mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes in Arhgef2 knockout mice, respectively. Our study provides a critical insight into a mechanism by which defective Arhgef2 mediates m6A-tagged target mRNAs to impair neural differentiation.
