Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling
Abstract 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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05131-x |
| _version_ | 1828444924002959360 |
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| author | Ke-Yan Yang Song Zhao Haiping Feng Jiaqi Shen Yuwei Chen Si-Tong Wang Si-Jia Wang Yu-Xin Zhang Yun Wang Caixia Guo Hongmei Liu Tie-Shan Tang |
| author_facet | Ke-Yan Yang Song Zhao Haiping Feng Jiaqi Shen Yuwei Chen Si-Tong Wang Si-Jia Wang Yu-Xin Zhang Yun Wang Caixia Guo Hongmei Liu Tie-Shan Tang |
| author_sort | Ke-Yan Yang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-10T21:51:29Z |
| format | Article |
| id | doaj.art-110caca768da407a8b94165236041b75 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-10T21:51:29Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-110caca768da407a8b94165236041b752022-12-22T01:32:11ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811310.1038/s41419-022-05131-xCa2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signalingKe-Yan Yang0Song Zhao1Haiping Feng2Jiaqi Shen3Yuwei Chen4Si-Tong Wang5Si-Jia Wang6Yu-Xin Zhang7Yun Wang8Caixia Guo9Hongmei Liu10Tie-Shan Tang11State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesBeijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences/China National Center for BioinformationState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesBeijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences/China National Center for BioinformationState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41419-022-05131-x |
| spellingShingle | Ke-Yan Yang Song Zhao Haiping Feng Jiaqi Shen Yuwei Chen Si-Tong Wang Si-Jia Wang Yu-Xin Zhang Yun Wang Caixia Guo Hongmei Liu Tie-Shan Tang Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling Cell Death and Disease |
| title | Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling |
| title_full | Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling |
| title_fullStr | Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling |
| title_full_unstemmed | Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling |
| title_short | Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling |
| title_sort | ca2 homeostasis maintained by tmco1 underlies corpus callosum development via erk signaling |
| url | https://doi.org/10.1038/s41419-022-05131-x |
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