來自中科院動(dòng)物研究所,,清華大學(xué)生科院的研究人員發(fā)現(xiàn)了果蠅生殖干細(xì)胞分化的一種新機(jī)制,,并且這一機(jī)制也可以延伸到斑馬魚和人類細(xì)胞,這對于分析生殖干細(xì)胞分化機(jī)制具有重要的意義,。這一研究成果公布在上周的Cell雜志上,。
文章的通訊作者是中科院動(dòng)物研究所的陳大華研究員,這位入選“百人計(jì)劃”,,獲得國家基金委杰出青年資助的研究人員在干細(xì)胞分裂機(jī)制等方面取得了許多重要成果,,其研究組的主要研究方向是以果蠅和小鼠等模式動(dòng)物作為模型系統(tǒng),研究干細(xì)胞分裂和分化以及個(gè)體衰老與長壽的分子機(jī)制,。
干細(xì)胞是生物體內(nèi)少數(shù)處于無限增殖,,未分化或低分化狀態(tài)并具有多種或一種分化潛能的細(xì)胞群。干細(xì)胞的獨(dú)特能力表現(xiàn)在于,,通過不對稱分裂產(chǎn)生具有相反命運(yùn)的兩個(gè)子代細(xì)胞,,一個(gè)是通過自我更新,重新產(chǎn)生維持干細(xì)胞特性的新干細(xì)胞,;而另一個(gè)子細(xì)胞則步入分化程序,,進(jìn)而形成新的組織,或替代生物體中損傷或丟失的組織和器官以維持生命活動(dòng)的延續(xù),。而生殖干細(xì)胞如何維持其未分化狀態(tài)是這一領(lǐng)域的一項(xiàng)核心課題,。
之前的研究顯示,骨形成蛋白(BMP)對于維持果蠅生殖干細(xì)胞的未分化狀態(tài)具有重要的意義,,這種作用因子可以通過分化因子Bam,,抑制生殖干細(xì)胞的分化,但是這一具體的過程,,至今科學(xué)家們還不是很清楚,。
在這篇文章中,研究人員發(fā)現(xiàn)一種絲氨酸/蘇氨酸激酶:Fused (Fu)能調(diào)控Hedgehog,,并與Smurf形成復(fù)合物,,通過BMP應(yīng)答系統(tǒng)操縱果蠅生殖干細(xì)胞的命運(yùn),而且研究人員在斑馬魚,,以及人類細(xì)胞中也發(fā)現(xiàn)了相似的作用,,這說明這一新機(jī)制可能具有廣泛的保守性。
去年陳大華研究組還發(fā)現(xiàn)了泛素介導(dǎo)的細(xì)胞周期蛋白在調(diào)控干細(xì)胞命運(yùn)方面的重要作用,,他們以果蠅生殖干細(xì)胞為研究對象,,發(fā)現(xiàn)泛素化過程相關(guān)的一種重要的基因effete——編碼一種泛素接合酶E2(Ubiquitin-conjugating Enzyme),在調(diào)控果蠅卵巢生殖干細(xì)胞的命運(yùn)決定中發(fā)揮重要作用,。
進(jìn)一步運(yùn)用遺傳學(xué),、生化及分子生物學(xué)等多種手段研究發(fā)現(xiàn),Eff蛋白通過結(jié)合有絲分裂后期促進(jìn)因子APC(一種多亞基的泛素連接酶E3)復(fù)合體中的dAPC2,,介導(dǎo)細(xì)胞周期蛋白——Cyclin A的泛素化,,從而通過調(diào)控Cyclin A蛋白水平的變化來影響生殖干細(xì)胞的命運(yùn),。這將泛素化信號(hào)通路調(diào)控與干細(xì)胞的命運(yùn)決定聯(lián)系起來,同時(shí)也表明了細(xì)胞周期調(diào)控因子直接控制干細(xì)胞的維持與分化,。泛素化機(jī)理和細(xì)胞周期調(diào)控機(jī)制從酵母到高等哺乳動(dòng)物高度保守,,說明哺乳動(dòng)物中可能存在相似的調(diào)控機(jī)制控制干細(xì)胞的命運(yùn)。(生物谷Bioon.com)
生物谷推薦原文出處:
Cell doi:10.1016/j.cell.2010.11.022
The Fused/Smurf Complex Controls the Fate of Drosophila Germline Stem Cells by Generating a Gradient BMP Response
Authors
Laixin Xia, Shunji Jia, Shoujun Huang, Hailong Wang, Yuanxiang Zhu, Yanjun Mu, Lijuan Kan, Wenjing Zheng, Di Wu, Xiaoming Li, Qinmiao Sun, Anming Meng, Dahua Chensend emailSee Affiliations
Highlights
CB differentiation involves antagonism of BMP signaling through regulation of Tkv
Fu regulates CB differentiation by antagonizing BMP signal via interaction with Tkv
Fu acts in concert with Smurf to terminate BMP signal by ubiquitinating Tkv in CBs
Fu has a conserved role in antagonizing BMP/TGFβ signals from fly to vertebrate
Summary
In the Drosophila ovary, germline stem cells (GSCs) are maintained primarily by bone morphogenetic protein (BMP) ligands produced by the stromal cells of the niche. This signaling represses GSC differentiation by blocking the transcription of the differentiation factor Bam. Remarkably, bam transcription begins only one cell diameter away from the GSC in the daughter cystoblasts (CBs). How this steep gradient of response to BMP signaling is formed has been unclear. Here, we show that Fused (Fu), a serine/threonine kinase that regulates Hedgehog, functions in concert with the E3 ligase Smurf to regulate ubiquitination and proteolysis of the BMP receptor Thickveins in CBs. This regulation generates a steep gradient of BMP activity between GSCs and CBs, allowing for bam expression on CBs and concomitant differentiation. We observed similar roles for Fu during embryonic development in zebrafish and in human cell culture, implying broad conservation of this mechanism.