The Super Elongation Complex Drives Neural Stem Cell Fate Commitment
The Super Elongation Complex Drives Neural Stem Cell Fate Commitment
复制标题
超级伸长复合物驱动神经干细胞的命运承诺。
DOI：
10.1016/j.devcel.2017.02.022
复制
发表时间：
2017-03-27
影响因子：
11.8
通讯作者：
Song, Yan
中科院分区：
文献类型：
--
作者：
Liu, Kun;Shen, Dan;Song, Yan
不对称的干细胞分裂在干细胞和其分化的兄弟细胞之间建立了初始差异，这对于维持稳态和防止癌变至关重要。然而，巩固和锁定这种最初的命运偏见的机制仍然不清楚。在这里，我们使用果蝇成神经细胞，以证明超延伸复合物（SEC）作为一个内在的放大器，以驱动细胞的命运承诺。SEC在成神经细胞中高度表达，在那里它通过与Notch转录激活复合物物理结合并增强HES（hairy和E（spl））转录来促进自我更新。HES反过来上调SEC活动，与SEC形成意想不到的自我强化反馈回路。SEC失活导致成神经细胞损失，而其强制激活导致神经祖细胞去分化和肿瘤发生。我们的研究揭示了SEC介导的细胞内放大器机制，以确保干细胞命运承诺的鲁棒性和精确性，并为SEC过度激活与人类癌症的高度频繁关联提供了机制解释。
Asymmetric stem cell division establishes an initial difference between a stem cell and its differentiating sibling, critical for maintaining homeostasis and preventing carcinogenesis. Yet the mechanisms that consolidate and lock in such initial fate bias remain obscure. Here, we use Drosophila neuroblasts to demonstrate that the super elongation complex (SEC) acts as an intrinsic amplifier to drive cell fate commitment. SEC is highly expressed in neuroblasts, where it promotes self-renewal by physically associating with Notch transcription activation complex and enhancing HES (hairy and E(spl)) transcription. HES in turn upregulates SEC activity, forming an unexpected self-reinforcing feedback loop with SEC. SEC inactivation leads to neuroblast loss, whereas its forced activation results in neural progenitor dedifferentiation and tumorigenesis. Our studies unveil an SEC-mediated intracellular amplifier mechanism in ensuring robustness and precision in stem cell fate commitment and providemechanistic explanation for the highly frequent association of SEC overactivation with human cancers.