近日，国际杂志《当代生物学》（Current Biology）在线刊登了中科院动物研究所研究人员的最新研究成果“The Niche-Dependent Feedback Loop Generates a BMP Activity Gradient to Determine the Germline Stem Cell Fate，”，文章中，研究者在细胞在微环境中动态调控研究获进展。
成体干细胞通过与微环境相互作用精确地控制自身的维持和分化。然而，人们却很少知道来自微环境的信号是如何动态和差异地在干细胞及其分化子细胞中传导并发挥作用，进而导致干细胞的不对称分裂。
中科院动物研究所陈大华实验室和陶毅实验室利用果蝇生殖干细胞作为研究对象，对发育生物学中这一基本科学问题进行了有意义的探讨，并取得了重要进展。他们发现，促分化蛋白Fused在分化子细胞（CB）中高表达而在干细胞（GSC）中低表达。进一步的分析发现，Fused的表达依赖微环境中BMP信号通路的强度。BMP受体Tkv与Fused的相互拮抗作用产生了一个陡峭的BMP浓度梯度，从而决定了干细胞及其分化子细胞自我更新和分化的不同命运。
有趣的是，作者们发现BMP活性梯度与Fused介导的拮抗BMP活性梯度以双稳形式在分化前体细胞pre-CB业已形成，由此动态地控制着分化主基因bam的表达水平在GSC与CB之间转换。分子系统动力学的研究进一步揭示了决定GSC命运的反馈调控机制的双稳态结构。分子生物学的证据清楚地表明，在干细胞分化过程中双稳态结构的形成主要依赖于依赖外源BMP信号的强度。
这些结果对于理解微环境信号控制干细胞不对称分裂及内源BMP响应梯度的物理机制有着重要意义，并可以对干细胞的行为进行预测。果蝇生殖干细胞不对称分裂的双稳态模型可能推广到多数的干细胞系统（包括哺乳动物的成体干细胞），对未来相关领域的研究具有指导意义。（生物谷Bioon.com）
doi:10.1016/j.cub.2012.01.056
PMC:
PMID:
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.
