2012年6月10日，國際權(quán)威學術(shù)期刊Nature Cell Biology在線發(fā)表了中國科學院生物化學與細胞生物學研究所朱學良組的研究論文“miR-129-3p controls cilia assembly by regulating CP110 and actin dynamics”。該研究揭示了小RNA介導的轉(zhuǎn)錄后調(diào)控調(diào)節(jié)纖毛發(fā)生的機理。
纖毛(cilium)是廣泛分布于動物組織中的一種突出于細胞表面的細胞器，根據(jù)功能的不同可分為初級纖毛和動纖毛兩類,，前者負責多種重要信號通路的傳遞，后者則是細胞 的一種運動器官。纖毛的發(fā)生首先需要將母中心粒（mother centriole）轉(zhuǎn)變成基體（basal body）,，而這一過程需要將CP110蛋白從母中心粒上去除；另外,，微絲的變化對纖毛發(fā)生也很重要,，但是目前尚不清楚這兩個過程是如何被調(diào)控的。小RNA（microRNA）則是近年來發(fā)現(xiàn)的能通過結(jié)合信使RNA尾部非翻譯區(qū)來抑制其編碼的蛋白質(zhì)水平的一種非編碼RNA,。
朱學良研究組研究生曹景利,、沈義棟和副研究員鄢秀敏等發(fā)現(xiàn)，一種叫做miR-129-3p的小RNA能夠以不依賴于細胞周期的方式在體外培養(yǎng)的哺乳類細胞中誘導初級纖毛的發(fā)生,，并闡明了其作用機理,。他們發(fā)現(xiàn)miR-129-3p通過下調(diào)中心體蛋白質(zhì)CP110和四個分枝狀微絲的調(diào)節(jié)因子的蛋白質(zhì)水平，從而促進母中心體向基體的轉(zhuǎn)換和與纖毛形成相關(guān)的囊泡在基體周圍的富集,，最終促進纖毛的發(fā)生和延伸,。小鼠中，miR-129-3p在富含初級纖毛的腦,、視網(wǎng)膜,、腎臟等組織中高表達,。利用模式生物斑馬魚，證明miR-129-3p調(diào)節(jié)斑馬魚發(fā)育過程中的纖毛發(fā)生,。抑制miR-129-3p會引起斑馬魚身體彎曲,、心包囊水腫、內(nèi)臟左右不對稱性紊亂等典型的纖毛病征,，纖毛的長度和數(shù)目也明顯減少,。這些發(fā)現(xiàn)不僅揭示小RNA可以調(diào)控初級纖毛的發(fā)生，提示miR-129-3p的突變可能也是人類纖毛病的病因之一,，而且還明確地把纖毛發(fā)生與分枝狀微絲形成的抑制聯(lián)系起來,。此外，由于去掉培養(yǎng)基中的血清,，即血清饑餓,，也能抑制分枝狀微絲的產(chǎn)生，這些研究結(jié)果部分地解釋了血清饑餓可高效誘導培養(yǎng)細胞產(chǎn)生纖毛的原因,。
該課題獲得了國家科技部,、國家自然科學基金委和中國科學院的經(jīng)費支持。（生物谷Bioon.com）
doi:10.1038/ncb2512
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miR-129-3p controls cilia assembly by regulating CP110 and actin dynamics
Jingli Cao, Yidong Shen, Lei Zhu, Yanan Xu, Yizhuo Zhou, Zhili Wu, Yiping Li, Xiumin Yan & Xueliang Zhu
Ciliogenesis requires the removal of CP110 from the mother centriole; actin dynamics also influence ciliation, at least partly by affecting the centrosomal accumulation of ciliogenic membrane vesicles. How these distinct processes are properly regulated remains unknown. Here we show that miR-129-3p, a microRNA conserved in vertebrates, controlled cilia biogenesis in cultured cells by concomitantly downregulating CP110 and repressing branched F-actin formation. Blocking miR-129-3p inhibited serum-starvation-induced ciliogenesis, whereas its overexpression potently induced ciliation in proliferating cells and also promoted cilia elongation. Gene expression analysis further identified ARP2, TOCA1, ABLIM1 and ABLIM3 as its targets in ciliation-related actin dynamics. Moreover, miR-129-3p inhibition in zebrafish embryos suppressed ciliation in Kupffer’s vesicle and the pronephros, and induced developmental abnormalities including a curved body, pericardial oedema and defective left–right asymmetry. Therefore, our results reveal a mechanism that orchestrates both the centriole-to-basal body transition and subsequent cilia assembly through microRNA-mediated post-transcriptional regulation.
