A PUF Hub Drives Self-Renewal in Caenorhabditis elegans Germline Stem Cells
A PUF Hub Drives Self-Renewal in Caenorhabditis elegans Germline Stem Cells
复制标题
DOI：
10.1534/genetics.119.302772
复制
发表时间：
2020-01-01
期刊：
影响因子：
3.3
通讯作者：
Kimble, Judith
中科院分区：
文献类型：
--
作者：
Haupt, Kimberly A.;Law, Kimberley T.;Kimble, Judith
干细胞调控依赖于来自生态位的外部信号以及干细胞内部响应和驱动自我更新的内在因素。先天的，生态位信号的缺失和内在自我更新因子的缺失可能会导致干细胞缺陷。然而，这个简单的预测并没有在大多数干细胞中得到证实，包括秀丽隐杆线虫生殖系干细胞（GSCs）。秀丽隐杆线虫GSCs的主要调控因子包括来自生态位的外源性作用/Notch信号；PUF家族中的内在作用rna结合蛋白，称为和（统称为FBF）；以及内在作用的PUF伴侣蛋白，它们是Notch的直接靶点。与缺失和缺失相比，缺失Notch信号或其靶标会产生更早、更严重的GSC缺陷，这表明一定存在额外的内在调节因子。在这里，我们报告这些缺失的调节因子是两个额外的PUF蛋白，和。值得注意的是，一个；四重零突变体的GSC缺陷与Notch零突变体的GSC缺陷几乎相同。两者都影响GSC的维持，两者都在GSC中表达，上位性实验将它们与FBF在网络中的位置相同。因此，和的作用解释了突变体中较轻的GSC缺陷。我们得出结论，一个由四个PUF蛋白和两个PUF伙伴组成的“PUF枢纽”构成了秀丽隐杆线虫GSC RNA调控网络的内在自我更新节点。该中心的发现强调了PUF rna结合蛋白作为干细胞维持的关键调节因子的重要性。
Stem cell regulation relies on extrinsic signaling from a niche plus intrinsic factors that respond and drive self-renewal within stem cells. A priori, loss of niche signaling and loss of the intrinsic self-renewal factors might be expected to have equivalent stem cell defects. Yet this simple prediction has not been borne out for most stem cells, including Caenorhabditis elegans germline stem cells (GSCs). The central regulators of C. elegans GSCs include extrinsically acting /Notch signaling from the niche; intrinsically acting RNA-binding proteins in the PUF family, termed and (collectively FBF); and intrinsically acting PUF partner proteins that are direct Notch targets. Abrogation of either /Notch signaling or its targets yields an earlier and more severe GSC defect than loss of and , suggesting that additional intrinsic regulators must exist. Here, we report that those missing regulators are two additional PUF proteins, and . Remarkably, an ; quadruple null mutant has a GSC defect virtually identical to that of a /Notch null mutant. and both affect GSC maintenance, both are expressed in GSCs, and epistasis experiments place them at the same position as FBF within the network. Therefore, action of and explains the milder GSC defect in mutants. We conclude that a "PUF hub," comprising four PUF proteins and two PUF partners, constitutes the intrinsic self-renewal node of the C. elegans GSC RNA regulatory network. Discovery of this hub underscores the significance of PUF RNA-binding proteins as key regulators of stem cell maintenance.