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Muscarinic receptor M3 contributes to intestinal stem cell maintenance via EphB/ephrin-B signaling.
Life Science Alliance ( IF 3.3 ) Pub Date : 2021-07-09 , DOI: 10.26508/lsa.202000962
Toshio Takahashi 1 , Akira Shiraishi 2 , Jun Murata 2 , Shin Matsubara 2 , Satsuki Nakaoka 3 , Shinji Kirimoto 3 , Masatake Osawa 4, 5
Affiliation  

Acetylcholine (ACh) signaling through activation of nicotinic and muscarinic ACh receptors regulates expression of specific genes that mediate and sustain proliferation, differentiation, and homeostasis in the intestinal crypts. This signaling plays a pivotal role in the regulation of intestinal stem cell function, but the details have not been clarified. Here, we performed experiments using type 3 muscarinic acetylcholine receptor (M3) knockout mice and their intestinal organoids and report that endogenous ACh affects the size of the intestinal stem niche via M3 signaling. RNA sequencing of crypts identified up-regulation of the EphB/ephrin-B signaling pathway. Furthermore, using an MEK inhibitor (U0126), we found that mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, which is downstream of EphB/ephrin-B signaling, is activated in M3-deficient crypts. Collectively, M3, EphB/ephrin-B, and the MAPK/ERK signaling cascade work together to maintain the homeostasis of intestinal epithelial cell growth and differentiation following modifications of the cholinergic intestinal niche.

中文翻译:

毒蕈碱受体 M3 通过 EphB/ephrin-B 信号传导有助于维持肠道干细胞。

乙酰胆碱 (ACh) 信号通过激活烟碱和毒蕈碱 ACh 受体调节特定基因的表达,这些基因介导和维持肠隐窝中的增殖、分化和稳态。这种信号传导在肠道干细胞功能的调节中起着关键作用,但细节尚未阐明。在这里,我们使用 3 型毒蕈碱乙酰胆碱受体 (M3) 敲除小鼠及其肠道类器官进行了实验,并报告内源性 ACh 通过 M3 信号传导影响肠道干生态位的大小。隐窝的 RNA 测序确定了 EphB/ephrin-B 信号通路的上调。此外,使用 MEK 抑制剂 (U0126),我们发现丝裂原活化蛋白激酶/细胞外信号调节激酶 (MAPK/ERK) 信号传导,它是 EphB/ephrin-B 信号的下游,在 M3 缺陷的隐窝中被激活。M3、EphB/ephrin-B 和 MAPK/ERK 信号级联共同作用以维持胆碱能小肠生态位修饰后肠上皮细胞生长和分化的稳态。
更新日期:2021-07-12
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