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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 (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.

SUBMITTER: Yang KY

PROVIDER: S-EPMC9352667 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.

Yang Ke-Yan KY Zhao Song S Feng Haiping H Shen Jiaqi J Chen Yuwei Y Wang Si-Tong ST Wang Si-Jia SJ Zhang Yu-Xin YX Wang Yun Y Guo Caixia C Liu Hongmei H Tang Tie-Shan TS

Cell death & disease 20220804 8

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 whit ...[more]

PMID: 35927240

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Project description:Objective: As a well-known traditional Chinese medicine formula prescribed by academician Ke-ji Chen, Qingda granule (QDG) lowered the blood pressure of spontaneously hypertensive rats and attenuated hypertensive cardiac remodeling and inflammation. However, its functional role and underlying mechanisms on hypertensive vascular function remain largely unclear. This study aims to assess the effects of QDG treatment on Angiotensin II- (AngII-) induced hypertension and vascular function and explore its underlying mechanisms both in vitro and in vivo. Methods: In an in vivo study, 25 male C57BL/6 mice were randomly divided into five groups, including Control, AngII, AngII + QDG-L, AngII + QDG-M, and AngII + QDG-H groups (n = 5 for each group). Mice in AngII and AngII + QDG-L/-M/-H groups were infused with AngII (500 ng/kg/min), while in the Control group, they were infused with saline. Mice in AngII + QDG were intragastrically given different concentrations of QDG (0.5725, 1.145, or 2.29 g/kg/day), while in Control and AngII groups, they were intragastrically given equal volumes of double distilled water for 2 weeks. Blood pressure was determined at 0, 1, and 2 weeks of treatment. Ultrasound was used to detect the pulse wave velocity (PWV) and HE staining to detect the pathological change of the abdominal aorta. RNA sequencing (RNA-seq) was performed to identify the differentially expressed transcripts (DETs) and related signaling pathways. IHC was used to detect the expression of p-ERK in the abdominal aorta. Primary isolated rat vascular smooth muscle cells (VSMCs) were used to assess the cellular Ca2+ release and activation of the ERK pathway by confocal microscope and western blotting analysis, respectively. Results: QDG treatment significantly alleviated the elevated blood pressure, the PWV, and the thickness of the abdominal aorta in AngII-induced hypertensive mice. RNA-seq and KEGG analyses identified 1,505 DETs and multiple enriched pathways (including vascular contraction and calcium signaling pathway) after QDG treatment. Furthermore, confocal microscope showed that QDG treatment partially attenuated the increase of Ca2+ release with the stimulation of AngII in cultured VSMCs. In addition, IHC and western blotting indicated that QDG treatment also partially alleviated the increase of phospho-ERK levels in abdominal aorta tissues of mice and cultured VSMCs after the infusion or stimulation of AngII. Conclusion: QDG treatment attenuated the elevation of blood pressure, abdominal aorta dysfunction, pathological changes, Ca2+ release, and activation of the ERK signaling pathway.

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Ca²⁺ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.

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Ca<sup>2+</sup> homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling.

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