Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage
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 Ca<sup>2+</sup> 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<sup>-/-</sup> OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a<sup>-/-</sup> OPCs in vitro and myelination in Tmem63a<sup>-/-</sup> 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 Ca<sup>2+</sup> influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Authors
- Xiao‐Yu Teng (ORCID: https://orcid.org/0000-0003-4631-6716)
- Dan Wu (ORCID: https://orcid.org/0000-0002-6661-2961)
- Fei Li (ORCID: https://orcid.org/0000-0003-0576-5849)
- Guifang Duan
- Yongkun Zhan
- Rong Xu (ORCID: https://orcid.org/0000-0001-5465-3566)
- Jianjun Yang (ORCID: https://orcid.org/0000-0001-6785-9627)
- Yun Xu (ORCID: https://orcid.org/0000-0001-5288-0319)
- Guiquan Chen (ORCID: https://orcid.org/0000-0002-4674-5548)
- Yun Stone Shi (ORCID: https://orcid.org/0000-0002-8842-9818)
- Linlin Zhang (ORCID: https://orcid.org/0000-0002-2644-4289)
- Yueying Wang (ORCID: https://orcid.org/0000-0001-8610-5804)
- Yongguo Yu
- Yan‐Yu Zang
- He Wang (ORCID: https://orcid.org/0009-0006-0344-4135)
Institutions
- Shanghai Jiao Tong University (CN)
- Peking University (CN)
- XinHua Hospital (CN)
- Guangdong Polytechnic of Science and Technology (CN)
- Nanjing Drum Tower Hospital (CN)
- Model Animal Research Center (CN)
- Luye Pharma (China) (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Neuroscience Bulletin
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1007/s12264-024-01338-4
- Citations
- 8
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Fundamental Research Funds for the Central Universities