2008年4月15日，動(dòng)物所陳大華研究員有關(guān)干細(xì)胞命運(yùn)調(diào)控的研究成果在國際著名的發(fā)育生物學(xué)雜志Developmental Cell上發(fā)表,。此項(xiàng)工作得到了科技部“生殖發(fā)育重大研究計(jì)劃”,、973項(xiàng)目和國家基金委重點(diǎn)項(xiàng)目以及中國科學(xué)院“百人計(jì)劃”的資助。
成體干細(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(duì)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),。干細(xì)胞不對(duì)稱分裂機(jī)制的研究是干細(xì)胞理論研究前沿中核心的課題。
核膜蛋白在染色質(zhì)組織,、基因調(diào)控,、信號(hào)轉(zhuǎn)導(dǎo)等方面起著非常重要的作用。然而至今這類蛋白的生理功能仍未闡明,。以果蠅為模型,，動(dòng)物研究所陳大華研究組發(fā)現(xiàn)了一個(gè)核膜蛋白Otefin (ote), 在維持果蠅生殖干細(xì)胞（GSC）自我更新過程中起關(guān)鍵調(diào)控作用。通過遺傳學(xué)方法,，研究者證明Ote是作為內(nèi)源因子來調(diào)節(jié)GSC命運(yùn)的因子,；進(jìn)一步機(jī)制研究表明，Ote蛋白通過調(diào)控BMP/Dpp信號(hào)途徑,，進(jìn)而關(guān)閉控制干細(xì)胞分化的關(guān)鍵bam基因的的轉(zhuǎn)錄表達(dá)來實(shí)現(xiàn)干細(xì)胞的自我更新,。通過結(jié)構(gòu)與功能的關(guān)系分析，研究者發(fā)現(xiàn)Ote蛋白作用位點(diǎn)為干細(xì)胞的核內(nèi)膜,，并由此推測Ote蛋白可能與BMP/Dpp信號(hào)途徑的核內(nèi)組分相互作用完成其功能,。通過生物化學(xué)方法研究者發(fā)現(xiàn)Ote能夠與Smad4/Medea直接發(fā)生相互作用，從而結(jié)合到bam沉默子上來調(diào)節(jié)GSC的命運(yùn),。該工作的意義在于：1,、證明了核膜蛋白參與干細(xì)胞的命運(yùn)調(diào)控，并可能推廣到哺乳動(dòng)物,；2,、為核膜蛋白如何參與TGFβ/BMP-介導(dǎo)的“基因沉默”提供初步的機(jī)制性解釋；3,、已知編碼核膜蛋白的導(dǎo)致人類的慢性疾病,，本工作可能為解析人類的核膜蛋白的編碼基因缺失相關(guān)疾病的發(fā)病機(jī)制提供一定線索。
生物谷推薦原始出處：
Developmental Cell, Vol 14, 494-506, 15 April 2008
Otefin, a Nuclear Membrane Protein, Determines the Fate of Germline Stem Cells in Drosophila via Interaction with Smad Complexes
Xiaoyong Jiang,1,2,3 Laixin Xia,1,2,3 Dongsheng Chen,1,2,3 Yingyue Yang,1,2 Haidong Huang,1,2 Lele Yang,1 Qiudong Zhao,1 Lijun Shen,1 Jun Wang,1 and Dahua Chen1,
1 State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuanxi Road, Haidian, Beijing, 100080, China
2 Graduate School, Chinese Academy of Sciences, 25 Beisihuanxi Road, Haidian, Beijing, 100080, China
Summary
Nuclear envelope proteins play important roles in chromatin organization, gene regulation, and signal transduction; however, the physiological role of these proteins remains elusive. We found that otefin (ote), which encodes a nuclear lamin, is essential for germline stem cell (GSC) maintenance. We show that Ote, as an intrinsic factor, is both necessary and sufficient to regulate GSC fate. Furthermore, we demonstrate that ote is required for the Dpp/BMP signaling pathway to silence bam transcription. By structure-function analysis, we demonstrate that the nuclear membrane localization of Ote is essential for its role in GSC maintenance. Finally, we show that Ote physically interacts with Medea/Smad4 at the bam silencer element to regulate GSC fate. Thus, we demonstrate that specific nuclear membrane components mediate signal-dependent transcriptional effects to control stem cell behavior.
