Requirement of Gα_q/Gα₁₁ Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis

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• 作者：Noboru Watanabe¹ ; Hirosato Mashima¹ ; ² ; ^{hmashima1-tky@umin.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Kouichi Miura¹ ; Takashi Goto¹ ; Makoto Yoshida³ ; Akiteru Goto³ ; Hirohide Ohnishi¹
• 关键词：Paneth Cell ; Intermediate Cell ; Wnt ; Gnaq ; Gna11
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：2
• 期：6
• 页码：767-782.e6
• 全文大小：7768 K

文摘

Proliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein–coupled receptors. We herein investigated the role of Gα_q/11-mediated signaling in intestinal homeostasis.

Methods

Intestinal tissues from control (Gnaq^flox/floxGna11^+/+), Int-G_q knock-out (KO) (VilCre^+/-Gnaq^flox/floxGna11^+/+), G₁₁ KO (Gnaq^flox/floxGna11^-/-), and Int-G_q/G₁₁ double knock-out (DKO) (VilCre^+/-Gnaq^flox/floxGna11^-/-) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gα_q/11-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gα_q/11 in colon.

Results

Paneth cells were enlarged, increased in number, and mislocalized in Int-Gq/G11 DKO small intestine. Paneth cells also reacted with PAS and Muc2 antibody, indicating an intermediate character of Paneth and goblet cells. The nuclear β-catenin, T-cell factor 1, and Sox9 expression were reduced severely in the crypt base of Int-Gq/G11 DKO intestine. Proliferation was activated in the crypt base and apoptosis was enhanced along the crypt. Int-Gq/G11 DKO mice were susceptible to DSS colitis. Proliferation was inhibited in the crypt of unaffected and regenerative areas. Cystic crypts, periodic acid–Schiff–positive cells, and Muc2-positive cells were unusually observed in the ulcerative region.

Conclusions

The Gα_q/11-mediated pathway plays a pivotal role in the preservation of intestinal homeostasis, especially in Paneth cell maturation and positioning. Wnt/β-catenin signaling was reduced significantly in the crypt base in Gα_q/G₁₁-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis.