Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling
Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling
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DOI：
10.1242/dev.141549
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发表时间：
2016-10
期刊：
影响因子：
4.6
通讯作者：
Y. Takada;A. Fukuda;T. Chiba;H. Seno
中科院分区：
文献类型：
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作者：
Y. Takada;A. Fukuda;T. Chiba;H. Seno
BRG1是SWI/SNF染色质重塑复合体的核心亚单位，对各种器官的发育和动态平衡是必不可少的。然而，BRG1在肠道发育和内稳态中的功能作用以及潜在的分子机制仍不清楚。我们发现，小鼠肠道中BRG1基因的缺失导致生长障碍和早期死亡，伴随着隐窝绒毛的异常形成，向分泌谱系细胞的偏向分化，显著增加了细胞凋亡，并导致十二指肠干细胞丢失。此外，我们发现在BRG1缺陷的十二指肠中，Notch信号通路显著下调。值得注意的是，Notch1细胞间域(ICD)的过表达部分逆转了肠道BRG1突变小鼠的预后。在BRG1缺陷的十二指肠中，NOTCH1 ICD的过表达挽救了形态发生，防止了向分泌谱系细胞的过度分化，并将细胞凋亡恢复到正常水平，尽管干细胞丢失无法挽救。我们的数据表明，BRG1在十二指肠的发育和动态平衡中发挥着重要作用，包括形态发生、干细胞分化和细胞存活。从机制上讲，Notch1 ICD的过表达挽救了肠道BRG1突变表型，表明Notch信号是介导BRG1效应的关键下游靶点。摘要：BRG1是SWI/SNF染色质重塑复合体的核心亚单位，通过调节Notch通路配体的表达，调节十二指肠的形态发生、分化和细胞存活。
Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1. Summary: Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, regulates morphogenesis, differentiation and cell survival of the duodenum, by modulating expression of Notch pathway ligands.