Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal.
Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal.
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DOI：
10.1038/nature22313
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发表时间：
2017-05-11
期刊：
影响因子：
64.8
通讯作者：
Kuo CJ
中科院分区：
文献类型：
--
作者：
Yan KS;Janda CY;Chang J;Zheng GXY;Larkin KA;Luca VC;Chia LA;Mah AT;Han A;Terry JM;Ootani A;Roelf K;Lee M;Yuan J;Li X;Bolen CR;Wilhelmy J;Davies PS;Ueno H;von Furstenberg RJ;Belgrader P;Ziraldo SB;Ordonez H;Henning SJ;Wong MH;Snyder MP;Weissman IL;Hsueh AJ;Mikkelsen TS;Garcia KC;Kuo CJ
经典的Wnt/β-catenin信号通路控制着不同的发育、稳态和病理过程。棕榈酰化的Wnt配体与细胞表面卷曲（Fzd）受体和Lrp 5/6共受体结合，使β-连环蛋白核转位和Tcf/Lef-dependent基因反式激活成为可能。Wnt下游信号传导组分的突变揭示了推测归因于Wnt配体本身的多种功能，尽管直接归因仍然难以捉摸，因为19种哺乳动物Wnt和10种Fzds之间的冗余以及Wnt疏水性使其复杂化。例如，单个Wnt配体突变尚未揭示肠上皮中的稳态表型，肠上皮是典型的典型Wnt途径依赖性快速自我更新组织，其再生由增殖性隐窝Lgr 5+肠干细胞（ISC）推动。Rspondin配体（Rspo 1 -4）与不同的Lgr 4 -6和Rnf 43/Znrf 3受体类别结合，显著增强经典Wnt/β-连环蛋白信号传导，并在体外诱导肠类器官生长和在体内诱导Lgr 5 + ISC。然而，Wnt与Rspo配体的互换性、功能合作以及对体内经典Wnt信号传导和ISC生物学的相对贡献仍然未知。在这里，我们解构了Wnt与Rspo配体在肠隐窝干细胞龛中的功能作用。我们证明了Lgr 5 + ISCs的默认命运是谱系承诺，逃避需要Rspo和Wnt配体。然而，使用Rspo与新型非脂化Wnt类似物的功能获得研究揭示了这些配体在ISCs中的定性不同的不可互换的作用。Wnt不足以诱导Lgr 5 + ISC自我更新，而是通过维持Rspo受体表达赋予基础能力，使Rspo能够主动驱动和指定干细胞扩增的程度。Wnt和Rspo配体之间的这种功能上不等同但合作的相互作用建立了通过不同的引发和自我更新因子调节哺乳动物干细胞的分子先例，对组织再生的精确控制具有广泛的意义。
The canonical Wnt/β-catenin signaling pathway governs diverse developmental, homeostatic and pathologic processes. Palmitoylated Wnt ligands engage cell surface Frizzled (Fzd) receptors and Lrp5/6 co-receptors enabling β-catenin nuclear translocation and Tcf/Lef-dependent gene transactivation. Mutations in Wnt downstream signaling components have revealed diverse functions presumptively attributed to Wnt ligands themselves, although direct attribution remains elusive, as complicated by redundancy between 19 mammalian Wnts and 10 Fzds and Wnt hydrophobicity. For example, individual Wnt ligand mutations have not revealed homeostatic phenotypes in the intestinal epithelium, an archetypal canonical Wnt pathway-dependent rapidly self-renewing tissue whose regeneration is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (Rspo1–4) engage distinct Lgr4-6 and Rnf43/Znrf3 receptor classes, markedly potentiate canonical Wnt/β-catenin signaling and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus Rspo ligands to in vivo canonical Wnt signaling and ISC biology remain unknown. Here, we deconstructed functional roles of Wnt versus Rspo ligands in the intestinal crypt stem cell niche. We demonstrate that the default fate of Lgr5+ ISCs is lineage commitment, escape from which requires both Rspo and Wnt ligands. However, gain-of-function studies using Rspo versus a novel non-lipidated Wnt analog reveal qualitatively distinct, non-interchangeable roles for these ligands in ISCs. Wnts are insufficient to induce Lgr5+ ISC self-renewal, but rather confer a basal competency by maintaining Rspo receptor expression that enables Rspo to actively drive and specify the extent of stem cell expansion. This functionally non-equivalent yet cooperative interplay between Wnt and Rspo ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precision control of tissue regeneration.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1073/pnas.96.7.3546
发表时间：
1999-03-30
影响因子：
11.1
作者：
Hsieh, JC;Rattner, A;Nathans, J
通讯作者：
Nathans, J
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
64.8
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
14.9
作者：
McCarthy DJ;Chen Y;Smyth GK
通讯作者：
Smyth GK