請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64322
標題: | GCM1標的基因high temperature requirement A4 (HtrA4)調控胎盤細胞融合及入侵的機制 A novel GCM1 target gene, high temperature requirement A4 (HtrA4), regulates placental cell fusion and invasion. |
作者: | Liang-Jie Wang 王亮傑 |
指導教授: | 陳宏文 |
關鍵字: | 胎盤細胞融合,胎盤細胞入侵, GCM1,HtrA4,trophoblast, |
出版年 : | 2012 |
學位: | 博士 |
摘要: | 細胞融合和細胞入侵在胎盤發育的過程扮演重要且不可或缺的角色。絨毛膜絨毛(chorionic villi)上的滋養葉胞層細胞 (cytotrophoblast)可透過細胞融合分化成多核的滋養葉融合層細胞 (syncytiotrophoblast),進而幫助養份和氣體的交換,另一方面,滋養葉胞層細胞透過分化形成外絨毛滋養細胞 (extravillous trophoblast),促使滋養細胞入侵到子宮組織,幫助母體和胎兒血液循環系統的交通。在我們過去的研究中發現,人類胎盤特殊轉錄因子GCM1 (Glial cells missing homolog 1)可透過控制融合蛋白syncytin-1和syncytin-2的基因表現來調控胎盤滋養葉細胞的細胞融合。值得一題的是,GCM1和syncytin-1蛋白都會在外絨毛滋養細胞中表現,然而,我們卻不知道它們在生理上的功能。為了探討此一問題,我們首先在胎盤細胞中證實GCM1具有促進胎盤細胞入侵的功能。我們進一步利用染色質免疫沉澱技術結合晶片分析(ChIP-chip analysis),鑑定發現HtrA4 (high temperature requirement A4)是GCM1獨特的標的基因,HtrA4蛋白具有絲氨酸蛋白酶的活性,透過切割fibronectin可幫助胎盤細胞的入侵功能。重要的是,透過免疫組織染色方法偵測到HtrA4蛋白位於胎盤和子宮的接觸面,並且發現HtrA4蛋白在缺氧環境的細胞和子癇先兆症病患的胎盤表現量明顯減少,顯示缺氧環境下HtrA4蛋白的減少可能造成外絨毛滋養細胞淺層入侵子宮組織,進而導致子癇先兆症。我們更進一步證實,HtrA4蛋白可直接和syncytin-1蛋白的SU區域結合,達到抑制細胞融合的功能。因此,HtrA4蛋白可能透過抑制細胞融合和促進細胞入侵的雙重角色,完成調控外絨毛滋養細胞分化的功能。在我們的研究中揭露了GCM1和HtrA4蛋白的新功能,具有調控外絨毛滋養細胞入侵的能力,並且證實異常HtrA4蛋白的表現可能導致子癇先兆症的形成。 Cell-cell fusion and cell invasion are essential for placental development. Human cytotrophoblasts in the chorionic villi may undergo cell-cell fusion to form syncytiotrophoblast to facilitate nutrient-gas exchange or differentiate into extravillous trophoblasts (EVTs) to facilitate maternal-fetal circulation. In our previous studies, the placental transcription factor, glial cell missing 1 (GCM1), regulates syncytin-1 and -2 expression to mediate trophoblast fusion. Interestingly, GCM1 and syncytin-1 are also expressed in EVTs with unknown physiological functions. We firstly demonstrated that GCM1 promote placental cells invasion. We also performed ChIP-chip analysis and identify high temperature requirement A4 (HtrA4) as a GCM1 novel target gene, which encodes a serine protease facilitating cleavage of fibronectin and invasion of placental cells. Importantly, HtrA4 is immunolocalized in EVTs at the maternal-fetal interface and its expression is decreased by hypoxia and in preeclampsia, a pregnancy complication associated with placental hypoxia and shallow trophoblast invasion. We further demonstrate that HtrA4 interacts with SU domain of syncytin-1 and suppresses cell-cell fusion. Therefore, HtrA4 may be crucial for EVT differentiation by playing a dual role in prevention of cell-cell fusion of EVTs and promotion of their invasion into the uterus. Our study reveals a novel function of GCM1 and HtrA4 in regulation of trophoblast invasion and that abnormal HrtA4 expression may contribute to shallow trophoblast invasion in preeclampsia. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64322 |
全文授權: | 有償授權 |
顯示於系所單位: | 生化科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-101-1.pdf 目前未授權公開取用 | 1.95 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。