Mechanisms of Uterine Estrogen Signaling During Early Pregnancy in Mice: an Update

56:3

i robertshaw and others Estrogen signaling in early 56:3 R127–R138 Review pregnancy

Mechanisms of uterine estrogen signaling during early pregnancy in mice: an update

I Robertshaw1,2, F Bian2,3 and S K Das2,3,4 Correspondence 1Department of Obstetrics and Gynecology, University of Cincinnati, West Chester, Ohio, USA should be addressed to 2Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA S K Das 3Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA E-mail 4Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA [email protected]

Abstract Key Words Adherence of an embryo to the uterus represents the most critical step of the ff estrogen reproductive process. Implantation is a synchronized event between the blastocyst and ff implantation the uterine luminal epithelium, leading to structural and functional changes for further ff uterus embryonic growth and development. The milieu comprising the complex process of ff pregnancy implantation is mediated by estrogen through diverse but interdependent signaling ff signaling pathways. Mouse models have demonstrated the relevance of the expression of estrogen- modulated paracrine factors to uterine receptivity and implantation window. More importantly, some factors seem to serve as molecular links between different estrogen pathways, promoting cell growth, acting as molecular chaperones, or amplifying estrogenic effects. Abnormal expression of these factors can lead to implantation failure and infertility. This review provides an overview of several well-characterized Journal of Molecular Endocrinology signaling pathways that elucidates the molecular cross talk involved in the uterus during Journal of Molecular Endocrinology early pregnancy. (2016) 56, R127–R138

Introduction

Reproduction is a fundamental aspect of life. The World that in a mouse, implantation occurs when the devel- Health Organization (WHO) has recognized infertility, oped blastocyst attaches to the luminal epithelium of the or the inability to reproduce, as a worldwide health uterine endometrium on the evening of day 4 of pregnancy concern with a lifetime prevalence ranging from 6.6 to (Enders & Schlafke 1969, Das et al. 1994). The attach- 26.4% (Boivin et al. 2007). Although much advancement ment of the embryo to the epithelial lining promotes the has been made using assisted reproductive technologies disappearance of epithelium. This depends on a mechanism (ARTs) to achieve higher pregnancy rates by improving of entosis (cell-eat-cell) by the trophoblast cells followed the selection of high-quality embryos, the implantation by apoptosis at the site of implantation (Parr et al. 1987, process is still very illusive. Li et al. 2015) and subsequent stimulation of stromal cell The development of the preimplantation embryo proliferation and differentiation into secretory decidual and the differentiation of the uterus are distinct processes cells. This series of events form the decidualization bed at occurring simultaneously in early gestation and must the blastocyst site (Huet-Hudson et al. 1989). be synchronized in order for successful implantation These structural and functional changes occurring in (Psychoyos 1973a, Paria et al. 1993). It has been shown the uterus promote receptivity to the invading blastocyst.

http://jme.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0300 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 04:01:35AM via free access

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mechanism oftheWnt/ gene promoters,suggestinganonclassicalinduction occupying acertainDNAregionofestrogen-responsive GPR30 signaling intheestrogen-dependentgeneregulation. sary evidence wasprovidedforanER a time-dependentmanner( and wasinterestinglyfoundtobeinteractingwithER confirmed intheepithelialcellsafterestrogenexposure immunofluorescence studies, estrogen-independent manner ( downstream effectors Similarly, studieshavealsoshownthatWnt/ without affectingearlyestrogeneffects( ulation of reported by( in theuterusanER-independentmanner, sinceas was suppressed rapidly by estrogen during the early phase growth phase is a result of the continuous presence of and proteinsynthesis.Analternate viewisthatthelate (18 occurring withinthefirst6 h, preparestheuterus forlater controversial. Oneconcept isthatanearlyevents(s), yet mechanismsinvolvedintheirregulationremain the uterus have been recognized for more than 70 years, Early (phaseI)andlateII)estrogenicresponses in phase IIestrogenic responses intheuterus Molecular linksbetween thephaseIand ER studies showthatGPR30canactasanegativeregulator of are insensitivetoG1intheaboveuterineeffects.Overall, studies should be considered to show that through theoff-targeteffectsofG1.Moreover, further noted thatthisstudywasunabletoexcludethepossibility is involved( stromal compartment, suggestingthat a paracrine signaling and ER early signalingevents,includingtheinhibitionofERK1/2 studies haveshownthatGPR30isinvolvedinregulating In contrast,usingselectiveactivationofGPR30byG1, ( uterine biologyisminimalforestrogenicgrowthregulation from in theuterineepithelialcells( mediated byE2.Inmouseuterus,GPR30localizesprimarily receptor, hasbeen implicated in earlynongenomicsignaling GPR30 (alsoknownasGPER1),aG-protein-coupled pregnancy Estrogen signalinginearly Wang Published byBioscientifica Ltd. α – -dependent uterinegrowthinresponsetoE2. 0 h)increaseinDNAsynthesis,cellproliferation, 30 Gpr30

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Journal of Molecular Endocrinology in anER-independentmanner butisstillrequiredforthe the expression of uterine NOP5/NOl5) ( protein SIK-similar(SIK-SP, alsoknownasNOP58/ of uterine estrogen signaling which involves a nucleolar cells. Arecentstudyhasuncoveredanunexpectedrole carries outtheassemblyofribosomalsubunitsineukaryotic The nucleolusisthenuclearsubdomainthatprimarily Role ofSik-SP estrogenicity andthereforemajorhealthconcerns. and xenoestrogenscanactasaplausibleriskfactorenhancing combination ofavarietysignalsinthebody, suchasstress, uterine estrogenicityforkepone( endogenous estrogen responseinmice,studieshavedemonstratedthat and theabilityofuterinegrowthviastress-induced with thenotionthatstresscanregulate mediated geneexpression( ER, whichinturnregulatesthekepone-dependentER induce sustainablelevelsofuterine estrogenicity. Specifically, thexenoestrogenkeponecan be potentiallyharmfulwithrespecttoenhanceduterine to theupregulationof and growth,thexenoestrogen-mediatedeffectswithregard of estrogen-dependent ER making them very potentestrogens( making themvery lowdosescomparabletotheirlevelofexposure, at very disruption. Furthermore,thesecompoundsareeffective sponding todistinctbiologicaleffectscausingendocrine activation intissuesexposedtoxenoestrogenscorre differences incoactivatorrecruitmentandtranscriptional defined ( target organfunction,yetthemechanismsarenotwell The abilitytobindER properties; hence,theyarecategorizedasxenoestrogens. tive toxicityisthoughttobeduetheirestrogen-like adverse effectsonhealthandreproduction.Thereproduc totheirpotentialfor gained attentionrecentlysecondary ants inmanyindustrial nations. These compoundshave rinated biphenyls,arehighlypersistentorganicpollut via estrogensignalinginthemouseuterus. those ofphaseIIforregulatedgrowthanddifferentiation Bip studies suggestthatthefunctionalactivationofER Bip DOI: 10.1530/JME-15-0300 http://jme.endocrinology-journals.org Review andER playsaroleincoordinatingphaseIresponseswith Knowing thecriticalrolethat Some organochlorinecompounds,suchaspolychlo Das α

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