PT  - JOURNAL ARTICLE
AU  - Toshio Takahashi
AU  - Akira Shiraishi
AU  - Jun Murata
AU  - Shin Matsubara
AU  - Satsuki Nakaoka
AU  - Shinji Kirimoto
AU  - Masatake Osawa
TI  - Muscarinic receptor M3 contributes to intestinal stem cell maintenance via EphB/ephrin-B signaling
AID  - 10.26508/lsa.202000962
DP  - 2021 Sep 01
TA  - Life Science Alliance
PG  - e202000962
VI  - 4
IP  - 9
4099  - https://www.life-science-alliance.org/content/4/9/e202000962.short
4100  - https://www.life-science-alliance.org/content/4/9/e202000962.full
SO  - Life Sci. Alliance2021 Sep 01; 4
AB  - 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.