Uterine Epithelial Gp130 Orchestrates Hormone Response and Epithelial Remodeling for Successful Embryo Attachment in Mice

Overview

Journal Sci Rep

Specialty Science

Date 2023 Jan 16

PMID 36646738

Authors

Takafumi Namiki

Jumpei Terakawa

Harumi Karakama

Michiko Noguchi

Hironobu Murakami

Yoshinori Hasegawa

Osamu Ohara

Takiko Daikoku

Junya Ito

Naomi Kashiwazaki

Affiliations

Soon will be listed here.

Abstract

Leukemia inhibitory factor (LIF) receptor, an interleukin 6 cytokine family signal transducer (Il6st, also known as Gp130) that is expressed in the uterine epithelium and stroma, has been recognized to play an essential role in embryo implantation. However, the molecular mechanism underlying Gp130-mediated LIF signaling in the uterine epithelium during embryo implantation has not been elucidated. In this study, we generated mice with uterine epithelium specific deletion of Gp130 (Gp130 ecKO). Gp130 ecKO females were infertile due to the failure of embryo attachment and decidualization. Histomorphological observation revealed that the endometrial shape and embryo position from Gp130 ecKO were comparable to those of the control, and uterine epithelial cell proliferation, whose attenuation is essential for embryo implantation, was controlled in Gp130 ecKO. Comprehensive gene expression analysis using RNA-seq indicates that epithelial Gp130 regulates the expression of estrogen- and progesterone-responsive genes in conjunction with immune response during embryo implantation. We also found that an epithelial remodeling factor, snail family transcriptional repressor 1 (Snai1), was markedly reduced in the pre-implantation uterus from Gp130 ecKO. These results suggest that not only the suppression of uterine epithelial cell proliferation, but also Gp130-mediated epithelial remodeling is required for successful implantation in mice.

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References

Zhang S, Lin H, Kong S, Wang S, Wang H, Wang H . Physiological and molecular determinants of embryo implantation. Mol Aspects Med. 2013; 34(5):939-80. PMC: 4278353. DOI: 10.1016/j.mam.2012.12.011. View

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

Stewart C, Kaspar P, Brunet L, Bhatt H, Gadi I, Kontgen F . Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992; 359(6390):76-9. DOI: 10.1038/359076a0. View

Kimura A, Kinjyo I, Matsumura Y, Mori H, Mashima R, Harada M . SOCS3 is a physiological negative regulator for granulopoiesis and granulocyte colony-stimulating factor receptor signaling. J Biol Chem. 2003; 279(8):6905-10. DOI: 10.1074/jbc.C300496200. View

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

Sherwin J, Freeman T, Stephens R, Kimber S, Smith A, Chambers I . Identification of genes regulated by leukemia-inhibitory factor in the mouse uterus at the time of implantation. Mol Endocrinol. 2004; 18(9):2185-95. DOI: 10.1210/me.2004-0110. View

Namiki T, Ito J, Kashiwazaki N . Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice. Reprod Med Biol. 2018; 17(4):331-342. PMC: 6194304. DOI: 10.1002/rmb2.12103. View

Fukui Y, Hirota Y, Matsuo M, Gebril M, Akaeda S, Hiraoka T . Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation. Reprod Med Biol. 2019; 18(3):234-240. PMC: 6613011. DOI: 10.1002/rmb2.12280. View

Sander L, Obermeier F, Dierssen U, Kroy D, Singh A, Seidler U . Gp130 signaling promotes development of acute experimental colitis by facilitating early neutrophil/macrophage recruitment and activation. J Immunol. 2008; 181(5):3586-94. DOI: 10.4049/jimmunol.181.5.3586. View

10.

Das S, Das N, Wang J, Lim H, Schryver B, Plowman G . Expression of betacellulin and epiregulin genes in the mouse uterus temporally by the blastocyst solely at the site of its apposition is coincident with the "window" of implantation. Dev Biol. 1997; 190(2):178-90. DOI: 10.1006/dbio.1997.8694. View

11.

Rodriguez C, Cheng J, Liu L, Stewart C . Cochlin, a secreted von Willebrand factor type a domain-containing factor, is regulated by leukemia inhibitory factor in the uterus at the time of embryo implantation. Endocrinology. 2003; 145(3):1410-8. DOI: 10.1210/en.2003-1361. View

12.

DeMayo F, Lydon J . 90 YEARS OF PROGESTERONE: New insights into progesterone receptor signaling in the endometrium required for embryo implantation. J Mol Endocrinol. 2019; 65(1):T1-T14. PMC: 7261627. DOI: 10.1530/JME-19-0212. View

13.

Kim H, Kim Y, Yoon J, Yang S, Park M, Seol D . Estrogen induces EGR1 to fine-tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation. FASEB J. 2017; 32(3):1184-1195. DOI: 10.1096/fj.201700854RR. View

14.

Cha J, Sun X, Dey S . Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012; 18(12):1754-67. PMC: 6322836. DOI: 10.1038/nm.3012. View

15.

Tranguch S, Chakrabarty A, Guo Y, Wang H, Dey S . Maternal pentraxin 3 deficiency compromises implantation in mice. Biol Reprod. 2007; 77(3):425-32. DOI: 10.1095/biolreprod.107.062414. View

16.

Noguchi M, Suzuki T, Sato R, Sasaki Y, Kaneko K . Artificial lactation by exogenous hormone treatment in non-pregnant sows. J Reprod Dev. 2020; 66(5):453-458. PMC: 7593638. DOI: 10.1262/jrd.2020-034. View

17.

Guo B, Tian X, Li D, Yang Z, Cao H, Zhang Q . Expression, regulation and function of Egr1 during implantation and decidualization in mice. Cell Cycle. 2014; 13(16):2626-40. PMC: 4614544. DOI: 10.4161/15384101.2014.943581. View

18.

Daikoku T, Cha J, Sun X, Tranguch S, Xie H, Fujita T . Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Dev Cell. 2011; 21(6):1014-25. PMC: 3241866. DOI: 10.1016/j.devcel.2011.09.010. View

19.

Kopylova E, Noe L, Touzet H . SortMeRNA: fast and accurate filtering of ribosomal RNAs in metatranscriptomic data. Bioinformatics. 2012; 28(24):3211-7. DOI: 10.1093/bioinformatics/bts611. View

20.

Wendt M, Balanis N, Carlin C, Schiemann W . STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT. 2014; 3(1):e28975. PMC: 4024059. DOI: 10.4161/jkst.28975. View