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)胞通常存在于一個特殊的微環(huán)境中,，微環(huán)境細(xì)胞通過信號分子完成與干細(xì)胞的相互作用,，進一步調(diào)控干細(xì)胞的命運，自我更新或分化,。
已知許多信號途徑參與干細(xì)胞的命運決定,，但干細(xì)胞及其分化子細(xì)胞如何差異地響應(yīng)和解讀源于微環(huán)境的信號，一直是干細(xì)胞生物學(xué)研究中懸而未決的基本科學(xué)問題之一,。
12月10日出版的Cell 雜志,，發(fā)表了中科院動物研究所陳大華等的一項最新研究成果，研究人員發(fā)現(xiàn)干細(xì)胞的分化子細(xì)胞通過Fused/Smurf復(fù)合體主動地拮抗來自微環(huán)境的BMP信號,，從而在干細(xì)胞和分化子細(xì)胞之間產(chǎn)生陡峭BMP響應(yīng)梯度,，進而促進干細(xì)胞不對稱地分裂。
作者還發(fā)現(xiàn)Fused和泛素連接酶Smurf形成的復(fù)合體,，共同調(diào)控BMP受體蛋白Tkv的泛素化,，進而調(diào)節(jié)其穩(wěn)定性。突變體的掃描分析表明,，Tkv238位的絲氨酸的磷酸化對Tkv的泛素化和穩(wěn)定性非常重要,，且Fused對Tkv穩(wěn)定性的調(diào)控,依賴該點的磷酸化。
陳大華實驗室還與清華大學(xué)孟安明實驗室合作,，以斑馬魚胚胎和人的細(xì)胞系為研究系統(tǒng),，進一步發(fā)現(xiàn)Fused在脊椎動物中同樣具有的拮抗BMP/TGF-?茁信號傳導(dǎo)的功能，從而揭示了Fused蛋白所介導(dǎo)的這一調(diào)控機制在進化上的保守性,，及其在干細(xì)胞命運調(diào)控和動物發(fā)育過程中細(xì)胞命運決定的重要作用,。（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
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 Chen
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.
