GLI2 Modulated by SUFU and SPOP Induces Intestinal Stem Cell Niche Signals in Development and Tumorigenesis
GLI2 Modulated by SUFU and SPOP Induces Intestinal Stem Cell Niche Signals in Development and Tumorigenesis
复制标题
DOI：
10.1016/j.celrep.2019.05.016
复制
发表时间：
2019-06-04
期刊：
影响因子：
8.8
通讯作者：
Kim, Tae-Hee
中科院分区：
文献类型：
--
作者：
Coquenlorge, Sabrina;Yin, Wen-Chi;Kim, Tae-Hee
肠道间充质提供关键的干细胞生态位信号，如Wnt配体，但这些信号是如何调节的尚不清楚。由于Hedgehog （Hh）信号对于肠道间质发育和肿瘤发生至关重要，我们通过分析缺失肠道间质中关键Hh信号负调控因子Sufu和/或Spop的小鼠，研究了Hh介导的机制，并证明了它们的剂量依赖性作用。尽管这些突变体表现出异常的间充质细胞生长和功能缺陷的肌肉层，绒毛化是通过适当的间充质聚集完成的，这意味着Hh信号的允许作用。这些间充质缺陷通过Gli2的还原得到部分修复。与发育过程中Hh异常激活导致上皮细胞增殖增加一致，Sufu减少促进肠道肿瘤发生，而Gli2杂合性抑制其发生。我们对染色质和GLI2结合基因组区域的分析揭示了其通过增强子对干细胞生态位信号的转录调控，为肠道干细胞生态位在发育和肿瘤发生中的机制提供了见解。
Gut mesenchyme provides key stem cell niche signals such as Wnt ligands, but how these signals are regulated is unclear. Because Hedgehog (Hh) signaling is critical for gut mesenchymal development and tumorigenesis, we investigated Hh-mediated mechanisms by analyzing mice deleted for key negative regulators of Hh signaling, Sufu and/or Spop, in the gut mesenchyme, and demonstrated their dosage-dependent roles. Although these mutants exhibit abnormal mesenchymal cell growth and functionally defective muscle layers, villification is completed with proper mesenchymal clustering, implying a permissive role for Hh signaling. These mesenchymal defects are partially rescued by Gli2 reduction. Consistent with increased epithelial proliferation caused by abnormal Hh activation in development, Sufu reduction promotes intestinal tumorigenesis, whereas Gli2 heterozygosity suppresses it. Our analyses of chromatin and GLI2 binding genomic regions reveal its transcriptional regulation of stem cell niche signals through enhancers, providing mechanistic insight into the intestinal stem cell niche in development and tumorigenesis.