近日,，國(guó)際雜志《當(dāng)代生物學(xué)》（Current Biology）在線刊登了中科院動(dòng)物研究所研究人員的最新研究成果“The Niche-Dependent Feedback Loop Generates a BMP Activity Gradient to Determine the Germline Stem Cell Fate,，”，文章中,，研究者在細(xì)胞在微環(huán)境中動(dòng)態(tài)調(diào)控研究獲進(jìn)展。
成體干細(xì)胞通過(guò)與微環(huán)境相互作用精確地控制自身的維持和分化,。然而,，人們卻很少知道來(lái)自微環(huán)境的信號(hào)是如何動(dòng)態(tài)和差異地在干細(xì)胞及其分化子細(xì)胞中傳導(dǎo)并發(fā)揮作用,，進(jìn)而導(dǎo)致干細(xì)胞的不對(duì)稱分裂。
中科院動(dòng)物研究所陳大華實(shí)驗(yàn)室和陶毅實(shí)驗(yàn)室利用果蠅生殖干細(xì)胞作為研究對(duì)象,，對(duì)發(fā)育生物學(xué)中這一基本科學(xué)問(wèn)題進(jìn)行了有意義的探討,，并取得了重要進(jìn)展。他們發(fā)現(xiàn),，促分化蛋白Fused在分化子細(xì)胞（CB）中高表達(dá)而在干細(xì)胞（GSC）中低表達(dá),。進(jìn)一步的分析發(fā)現(xiàn)，F(xiàn)used的表達(dá)依賴微環(huán)境中BMP信號(hào)通路的強(qiáng)度,。BMP受體Tkv與Fused的相互拮抗作用產(chǎn)生了一個(gè)陡峭的BMP濃度梯度,，從而決定了干細(xì)胞及其分化子細(xì)胞自我更新和分化的不同命運(yùn)。
有趣的是,，作者們發(fā)現(xiàn)BMP活性梯度與Fused介導(dǎo)的拮抗BMP活性梯度以雙穩(wěn)形式在分化前體細(xì)胞pre-CB業(yè)已形成,，由此動(dòng)態(tài)地控制著分化主基因bam的表達(dá)水平在GSC與CB之間轉(zhuǎn)換。分子系統(tǒng)動(dòng)力學(xué)的研究進(jìn)一步揭示了決定GSC命運(yùn)的反饋調(diào)控機(jī)制的雙穩(wěn)態(tài)結(jié)構(gòu),。分子生物學(xué)的證據(jù)清楚地表明,，在干細(xì)胞分化過(guò)程中雙穩(wěn)態(tài)結(jié)構(gòu)的形成主要依賴于依賴外源BMP信號(hào)的強(qiáng)度。
這些結(jié)果對(duì)于理解微環(huán)境信號(hào)控制干細(xì)胞不對(duì)稱分裂及內(nèi)源BMP響應(yīng)梯度的物理機(jī)制有著重要意義,，并可以對(duì)干細(xì)胞的行為進(jìn)行預(yù)測(cè),。果蠅生殖干細(xì)胞不對(duì)稱分裂的雙穩(wěn)態(tài)模型可能推廣到多數(shù)的干細(xì)胞系統(tǒng)（包括哺乳動(dòng)物的成體干細(xì)胞），對(duì)未來(lái)相關(guān)領(lǐng)域的研究具有指導(dǎo)意義,。（生物谷Bioon.com）
doi:10.1016/j.cub.2012.01.056
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The Niche-Dependent Feedback Loop Generates a BMP Activity Gradient to Determine the Germline Stem Cell Fate
Laixin Xia1, 4, Xiudeng Zheng2, 3, 4, Wenjing Zheng1, 4, Guoqiang Zhang1, 4, Hailong Wang1, Yi Tao2, 3, , , Dahua Chen1, ,
Stem cells interact with surrounding stromal cells (or niche) via signaling pathways to precisely balance stem cell self-renewal and differentiation [ [1], [2], [3] and [4]]. However, little is known about how niche signals are transduced dynamically and differentially to stem cells and their intermediate progeny and how the fate switch of stem cell to differentiating cell is initiated. The Drosophila ovarian germline stem cells (GSCs) have provided a heuristic model for studying the stem cell and niche interaction. Previous studies demonstrated that the niche-dependent BMP signaling is essential for GSC self-renewal via silencing bam transcription in GSCs [ [5], [6] and [7]]. We recently revealed that the Fused (Fu)/Smurf complex degrades the BMP type I receptor Tkv allowing for bam expression in differentiating cystoblasts (CBs) [8]. However, how the Fu is differentially regulated in GSCs and CBs remains unclear. Here we report that a niche-dependent feedback loop involving Tkv and Fu produces a steep gradient of BMP activity and determines GSC fate. Importantly, we show that Fu and graded BMP activity dynamically develop within an intermediate cell, the precursor of CBs, during GSC-to-CB transition. Our mathematic modeling reveals a bistable behavior of the feedback-loop system in controlling the bam transcriptional on/off switch and determining GSC fate.
