Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100190, China; Sino-Danish Center for Education and Research, Beijing, 100190, China; Shanghai Advanced Research Institute, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 201210, China; Department of Clinical Medicine, Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Aarhus, 8200, Denmark.
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Biochem Biophys Res Commun. 2022 Jan 22;589:71-77. doi: 10.1016/j.bbrc.2021.11.106. Epub 2021 Dec 3.
Hyccin/FAM126A mutations are linked to hypomyelination and congenital cataract disease (HCC), but whether and how Hyccin/FAM126A deficiency causes hypomyelination remains undetermined. This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila. Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma membrane-targeting recombinant mouse PI4KIIIα. Additionally, PI4KIIIα knockdown in glia phenocopied Hyccin/FAM126A knockdown, and this was partially rescued by overexpressing the recombinant PI4KIIIα, but not human FAM126A or FAM126B. This study establishes an animal model of HCC and indicates that Hyccin/FAM126A plays an essential role in glial enrichment and axonal sheath in a cell-autonomous manner in the visual system via controlling the expression and stabilization of the PI4KIIIα complex at the plasma membrane.
Hyccin/FAM126A 突变与少突胶质细胞发育不全和先天性白内障疾病（HCC）有关，但 Hyccin/FAM126A 缺乏是否以及如何导致少突胶质细胞发育不全仍未确定。本研究表明，Hyccin/FAM126A 的表达对于果蝇中 PI4KIIIα 复合物的其他成分的表达是必需的。在神经胶质细胞中敲低 Hyccin/FAM126A 会减少神经胶质细胞的富集，破坏视觉系统中的轴突鞘和视觉能力，而过表达人 FAM126A 或 FAM126B 可以完全挽救这些缺陷，而过表达膜靶向重组小鼠 PI4KIIIα 则可以部分挽救。此外，在神经胶质细胞中敲低 PI4KIIIα 可模拟 Hyccin/FAM126A 敲低，而过表达重组 PI4KIIIα可部分挽救，而过表达人 FAM126A 或 FAM126B 则不能挽救。本研究建立了 HCC 的动物模型，并表明 Hyccin/FAM126A 通过控制质膜上 PI4KIIIα 复合物的表达和稳定，以细胞自主的方式在视觉系统中发挥着对神经胶质细胞富集和轴突鞘形成的重要作用。
