Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage
Yue‑Ying Wang1,2,3 · Dan Wu1 · Yongkun Zhan4,5 · Fei Li6 · Yan‑Yu Zang1 · Xiao‑Yu Teng1,3 · Linlin Zhang7 · Gui‑Fang Duan8 · He Wang2 · Rong Xu9 · Guiquan Chen1 · Yun Xu1 · Jian‑Jun Yang2 · Yongguo Yu4,10 · Yun Stone Shi1,31 Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Neurology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210032, China
2 Department of Anesthesiology, Pain and Perioperative Medicine, First Afliated Hospital of Zhengzhou University, Zhengzhou 450052, China
3 Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai 519031, China
4 Center of Clinical Genetics, School of Medicine, Xinhua Hospital Afliated to Shanghai Jiao Tong University , Shanghai 200092, China
5 Shanghai Institute for Pediatric Research, Shanghai 200092, China
6 Department of Developmental and Behavioral Pediatrics, Department of Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital Afliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
7 Qilu Pharmaceutical Co., Ltd, Jinan 250100, China
8 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100091, China
9 Department of Rehabilitation Medicine, Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing 210008, China
Abstract
Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a−/− OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a−/− OPCs in vitro and myelination in Tmem63a−/− mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca2+ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Keywords
TMEM63A; Mutation; Oligodendrocyte diferentiation; Hypomyelination
