Ca(2+) homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.
Ca(2+) homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.
复制标题
由TMCO 1维持的Ca（2+）稳态是通过ERK信号传导的胼胝体发育的基础。
DOI：
10.1038/s41419-022-05131-x
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发表时间：
2022-08-04
影响因子：
9
通讯作者：
Tang, Tie-Shan
中科院分区：
文献类型：
--
作者：
Yang, Ke-Yan;Zhao, Song;Feng, Haiping;Shen, Jiaqi;Chen, Yuwei;Wang, Si-Tong;Wang, Si-Jia;Zhang, Yu-Xin;Wang, Yun;Guo, Caixia;Liu, Hongmei;Tang, Tie-Shan
跨膜螺旋结构域1 （TMCO1）在维持内质网（ER）钙（Ca2+）储存的稳态中起重要作用。tmco1缺陷综合征与人脑-面-胸（CFT）发育不良具有多种特征，包括胼胝体（CC）异常。在这里，我们报道TMCO1是通过维持Ca2+稳态来维持CC正常发育所必需的。Tmco1−/−小鼠表现出严重的CC发育，白质纤维束不能穿过中线。从机制上说，TMCO1缺乏引起的过量Ca2+信号导致FGFs上调和ERK过度激活，导致胶质细胞迁移过量，灰industrium中线胶质细胞过度聚集，在穿过中线之前，灰industrium分泌Slit2来阻止神经纤维束的延伸。因此，使用临床MEK抑制剂来减弱过度激活的FGF/ERK信号可以显著改善Tmco1−/−大脑中CC的形成。我们的研究结果不仅揭示了TMCO1缺陷综合征中CC异常的潜在机制，而且为减轻患者CC相关发病提供了一种有吸引力的预防策略。
Transmembrane of coiled-coil domains 1 (TMCO1) plays an important role in maintaining homeostasis of calcium (Ca2+) stores in the endoplasmic reticulum (ER). TMCO1-defect syndrome shares multiple features with human cerebro-facio-thoracic (CFT) dysplasia, including abnormal corpus callosum (CC). Here, we report that TMCO1 is required for the normal development of CC through sustaining Ca2+ homeostasis. Tmco1−/− mice exhibit severe agenesis of CC with stalled white matter fiber bundles failing to pass across the midline. Mechanistically, the excessive Ca2+ signals caused by TMCO1 deficiency result in upregulation of FGFs and over-activation of ERK, leading to an excess of glial cell migration and overpopulated midline glia cells in the indusium griseum which secretes Slit2 to repulse extension of the neural fiber bundles before crossing the midline. Supportingly, using the clinical MEK inhibitors to attenuate the over-activated FGF/ERK signaling can significantly improve the CC formation in Tmco1−/− brains. Our findings not only unravel the underlying mechanism of abnormal CC in TMCO1 defect syndrome, but also offer an attractive prevention strategy to relieve the related agenesis of CC in patients.
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