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Uterine Gα_q/11 signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.

ABSTRACT: A nonreceptive uterus is a major cause of embryo implantation failure. This study examined the importance of the Gα_q/11-coupled class of GPCRs as regulators of uterine receptivity. Mice were created lacking uterine Gα_q and Gα₁₁; as a result, signaling by all uterine Gα_q/11-coupled receptors was disrupted. Reproductive profiling of the knockout females revealed that on d 4 of pregnancy, despite adequate serum progesterone (P4) levels and normal P4 receptor (PR) expression, there was no evidence of PR signaling. This resulted in the down-regulation of heart and neural crest derivatives expressed 2, Kruppel-like factor 15, and cyclin G1 and the subsequent persistent proliferation of the luminal epithelium. Aquaporin (Aqp) 11 was also potently down-regulated, whereas Aqp5/AQP5 expression persisted, resulting in the inhibition of luminal closure. Hypertrophy of the myometrial longitudinal muscle was also dramatically diminished, likely contributing to the observed implantation failure. Further analyses revealed that a major mechanism via which uterine Gα_q/11 signaling induces PR signaling is through the transcriptional up-regulation of leucine-rich repeat-containing GPCR 4 (Lgr4). LGR4 was previously identified as a trigger of PR activation and signaling. Overall, this study establishes that Gα_q/11 signaling, in a P4-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse, and disruption of such signaling results in P4 resistance.-de Oliveira, V., Schaefer, J., Calder, M., Lydon, J. P., DeMayo, F. J., Bhattacharya, M., Radovick, S., Babwah, A. V. Uterine Gα_q/11 signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.

SUBMITTER: de Oliveira V

PROVIDER: S-EPMC6662978 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Uterine Gαq/11 signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.

de Oliveira Vanessa V Schaefer Jennifer J Calder Michele M Lydon John P JP DeMayo Francesco J FJ Bhattacharya Moshmi M Radovick Sally S Babwah Andy V AV

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20190515 8

A nonreceptive uterus is a major cause of embryo implantation failure. This study examined the importance of the Gαq/11-coupled class of GPCRs as regulators of uterine receptivity. Mice were created lacking uterine Gαq and Gα11; as a result, signaling by all uterine Gαq/11-coupled receptors was disrupted. Reproductive profiling of the knockout females revealed that on d 4 of pregnancy, despite adequate serum progesterone (P4) levels and normal P4 recep ...[more]

PMID: 31091422

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Project description:Background & aimsProliferation, 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 Gαq/11-mediated signaling in intestinal homeostasis.MethodsIntestinal tissues from control (Gnaqflox/floxGna11+/+ ), Int-Gq knock-out (KO) (VilCre+/-Gnaqflox/floxGna11+/+ ), G11 KO (Gnaqflox/floxGna11-/- ), and Int-Gq/G11 double knock-out (DKO) (VilCre+/-Gnaqflox/floxGna11-/- ) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gαq/11-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gαq/11 in colon.ResultsPaneth 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.ConclusionsThe Gαq/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 Gαq/G11-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis.

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Uterine Gα_q/11 signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.

Publications

Uterine Gα<sub>q/11</sub> signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse.

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