GDF15 deficiency hinders human trophoblast invasion to mediate pregnancy loss through downregulating Smad1/5 phosphorylation.
GDF15 deficiency hinders human trophoblast invasion to mediate pregnancy loss through downregulating Smad1/5 phosphorylation.
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DOI：
10.1016/j.isci.2023.107902
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发表时间：
2023-10-20
期刊：
影响因子：
5.8
通讯作者：
Li, Shan
中科院分区：
文献类型：
--
作者：
Zeng, Yu-Ting;Liu, Wen-Fang;Zhang, Peng-Sheng;Li, Shan
生长分化因子15（GDF 15）属于转化生长因子β（TGF-β）超家族。孕妇血清中GDF 15的降低与流产有关。免疫组化和酶联免疫吸附试验均显示，流产孕妇滋养层组织和血清中的GDF 15水平显著低于活产孕妇。通过CRIPSR编辑，GDF 15缺陷与GDF 15敲除小鼠中的胚胎吸收相关。此外，GDF 15还能促进HTR-8/SVneo和JEG-3细胞的迁移和侵袭能力。在机制上，GDF 1/5增加Smad 1/5磷酸化，导致上调SNAI 1/2、波形蛋白和下调E-钙粘蛋白。双荧光素酶报告基因分析证实，Smad结合元件（SBE）和/或GC丰富的基序被激活，靶基因，如SNAI 1/2，SERPINE 1，TIMP 3的转录调控GDF 15/Smad 5信号。因此，我们的数据揭示了GDF 1/5通过上调TGF-β/Smad 1/5通路的活性在滋养层细胞侵袭中的关键作用。滋养层细胞产生GDF 1/5，GDF 1/5通过自分泌和旁分泌模式发挥作用GDF 1/5通过与其受体结合使滋养层细胞中的Smad 1/5磷酸化磷酸化Smad 1/5激活靶基因，如SNAI 1/2，E-Cadherin，Vimentin生殖医学;分子生理学;发育生物学
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC and ELISA assays showed that GDF15 in trophoblast tissue and serum of pregnant women who miscarried was significantly lower than in those who had a live birth. GDF15 deficiency was associated with embryo resorption in GDF15 knockout mice through CRIPSR editing. In addition, the migration and invasion ability of HTR-8/SVneo and JEG-3 cells were promoted by GDF15. Mechanistically, GDF15 increased Smad1/5 phosphorylation, resulting in upregulating SNAI1/2, VIMENTIN and downregulating E-CADHERIN. A dual-luciferase reporter assay confirmed that Smad-binding elements (SBE) and/or GC-rich motifs were activated and target genes such as SNAI1/2, SERPINE1, and TIMP3 were transcriptionally regulated by GDF15/Smad5 signaling. Therefore, our data revealed a crucial role of GDF15 on invasion of trophoblast by upregulating the activity of TGF-β/Smad1/5 pathway. Trophoblastic cells produce GDF15 which works through autocrine and paracrine modes GDF15 phosphorylates Smad1/5 in trophoblast cells through binding to its receptor Phosphorylated Smad1/5 activates target genes, such as SNAI1/2, E-Cadherin, Vimentin Reproductive medicine; Molecular physiology; Developmental biology
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DOI：
10.1016/j.fct.2016.06.023
发表时间：
2016-12
期刊：
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
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作者：
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影响因子：
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影响因子：
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