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Epithelial Estrogen Receptor 1 Intrinsically Mediates Squamous Differentiation in the Mouse Vagina

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Epithelial Estrogen Receptor 1 Intrinsically Mediates Squamous Differentiation in the Mouse Vagina Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina Shinichi Miyagawaa,b and Taisen Iguchia,b,1 aOkazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; and bDepartment of Basic Biology, Faculty of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan Edited by Jan-Åke Gustafsson, University of Houston, Houston, Texas, and approved September 10, 2015 (received for review July 10, 2015) Estrogen-mediated actions in female reproductive organs are are definite requirements for epithelial ESR1 expression in uterine tightly regulated, mainly through estrogen receptor 1 (ESR1). The epithelial functionalization (e.g., lactoferrin gene expression and mouse vaginal epithelium cyclically exhibits cell proliferation and prevention of cell death in the uterus), as well as in ductal mor- differentiation in response to estrogen and provides a unique phogenesis, alveologenesis, and lactation in the mammary gland model for analyzing the homeostasis of stratified squamous ep- (11, 12). ithelia. To address the role of ESR1-mediated tissue events dur- Another female reproductive organ, the mouse vagina, exhibits a ing homeostasis, we analyzed mice with a vaginal epithelium- unique estrogen-responsive feature. The vaginal epithelium exhibits specific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). cyclical, estrogen-dependent cell proliferation and squamous dif- We show here that loss of epithelial ESR1 in the vagina resulted ferentiation during the estrous cycle. The vaginae of ovariectomized in aberrant epithelial cell proliferation in the suprabasal cell layers (OVX) mice show an atrophied epithelium with two to three cell and led to failure of keratinized differentiation. Gene expression layers, whereas estrogen administration rapidly induces epithe- analysis showed that several known estrogen target genes, includ- lial cell proliferation in the basal layer. The suprabasal cells are ing erbB growth factor ligands, were not induced by estrogen in no longer mitogenic but differentiate while moving up through the K5-Esr1KO mouse vagina. Organ culture experiments revealed the epithelium, resulting in keratinization of apical cells. The fully that the addition of erbB growth factor ligands, such as amphir- stratified and keratinized vaginal epithelium resembles the typi- egulin, could activate keratinized differentiation in the absence cal stratified and keratinized epidermis found in the skin and of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and other organs. growth factor signaling to mediate regulation of cell prolifera- The formation and maintenance of such epithelia relies on a tion in squamous differentiation, and our results provide new tightly balanced process of epithelial cell proliferation and squamous insights into estrogen-mediated homeostasis in female repro- differentiation. Classical tissue recombination experiments suggest ductive organs. that epithelial ESR1 in the vagina is dispensable for cell proliferation but is indispensable for squamous differentiation (5, 14). Until now, estrogen receptor | vagina | keratinization | amphiregulin | epithelium no mouse model for tissue-specific KO of Esr1 inthevaginahas been developed. In this study, we used genetic analysis of ESR1 strogens play important roles in vertebrate reproductive biology, function in the vagina by creating an epithelium-specific Esr1 KO to Ewith effects principally mediated through the nuclear estrogen provide new insights into the potential tissue-specific function of receptors (ESRs). ESRs are members of the nuclear receptor su- ESR1. We found that estrogen can induce cell proliferation in the perfamily and typically up-regulate gene transcription upon ligand absence of epithelial ESR1, but that the epithelial cells showed binding. Two different genes encoding the two ESR subtypes, ESR1 severe defects in keratinocyte commitment. We also found that (formerly named ERα) and ESR2 (formerly named ERβ), have amphiregulin (Areg) is required downstream of epithelial ESR1 been identified from a variety of vertebrate species. ESR1 is the for terminal differentiation in the epithelium. Thus, epithelial predominant subtype regulating estrogen-mediated proliferation and ESR1 integrates estrogen and growth factor signaling to mediate differentiation of female reproductive organs. Administration of es- the switch between cell proliferation and squamous cell differ- trogens increases organ weights and promotes cell proliferation and entiation in the mouse vagina. differentiation, whereas such events were not evoked in the Esr1- – deficient mice (1 3). Significance Estrogen actions on the uterus and mammary gland have been extensively analyzed. During the first step of estrogen action, – Estrogen regulation of tissue homeostasis, particularly the reg- epithelial stromal interactions play a pivotal role in epithelial ulation of cell proliferation and differentiation in female re- cell proliferation. In vitro tissue recombination experiments with productive organs, is interesting both in its basic biology and in Esr1 knockout (KO)- and wild-type-derived epithelium and several disease models and cancer biology. Using an epithelial stroma revealed that the effects of estrogen on uterine and estrogen receptor 1 (Esr1) conditional knockout mouse model, mammary epithelial cell proliferation are mediated primarily via we showed that vaginal epithelial cells lacking ESR1 failed to stromally expressed ESR1 (4-6). Estrogen-induced growth factors activate growth factor signaling and remained undifferentiated secreted from the stroma subsequently promote epithelial cell and in a proliferative state throughout the epithelium. Thus, – proliferation (7 10). Experiments using epithelial cell-specific KO epithelial ESR1 mediates the switch between cell proliferation of Esr1 revealed that estrogen can induce proliferation of uterine and squamous cell differentiation, demonstrating unique roles epithelial cells despite the absence of epithelial ESR1 (11). In of ESR1 in the female reproductive tract. contrast, similar experiments using a mammary epithelium-specific Esr1 KO showed that ESR1 is required in the epithelial cells for Author contributions: S.M. designed research; S.M. performed research; S.M. analyzed mammary gland growth and ductal epithelial cell proliferation (12). data; and S.M. and T.I. wrote the paper. It is uncertain whether these differences result from different The authors declare no conflict of interest. requirements for epithelial ESR1 in the uterus versus the mam- This article is a PNAS Direct Submission. mary gland or whether they result from methodological differences 1To whom correspondence should be addressed. Email: [email protected]. in tissue recombination experiments (e.g., age of donor, hormone This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. treatment protocol) (13). Irrespective of these differences, there 1073/pnas.1513550112/-/DCSupplemental. 12986–12991 | PNAS | October 20, 2015 | vol. 112 | no. 42 www.pnas.org/cgi/doi/10.1073/pnas.1513550112 Downloaded by guest on September 27, 2021 Results layers of the vaginal epithelium (Fig. 1 G and I). KRT14 was Phenotypes of Epithelial-Specific Esr1 KO Mice. ESR1 protein is expressed in basal and suprabasal cells but was absent in the apical expressed in both the vaginal epithelium and the stroma in the wild- cell layer in OVX and estrogen-treated K5-Esr1KO vaginae (Fig. 1 type mouse vagina (Fig. 1A). We generated a vaginal epithelial H and J). KRT8, a marker for undifferentiated cells, was expressed cell-specific Esr1 KO mouse model (K5-Esr1KO) by crossing in a few suprabasal cells in the control OVX mouse vagina, but its Esr1-floxed mice with K5-Cre transgenic lines that express Cre expression was augmented in theOVXK5-Esr1KOmice(Fig.1L). recombinase in the vaginal epithelial cells (15). ESR1 protein KRT8-positive cells were persistent in the apical layer of cells, even was detected in the stroma, but not in the epithelium, demon- after estrogen treatment in K5-EsR1KO mice (Fig. 1 M and N). strating the epithelium-specificity of Esr1 loss of function in the The stratified and squamous differentiation marker, KRT1, was K5-Esr1KO mouse vagina (Fig. 1B). We first tested whether expressed in the differentiating suprabasal cells upon estrogen- estrogen induced cell proliferation and/or differentiation in the treatment in the control mouse vagina. Intriguingly, it was not K5-Esr1KO mouse vagina, using OVX mice to avoid any con- detected in the K5-Esr1KO mice, although these animals did ex- founding effects of the hypothalamus-pituitary-gonadal axis and hibit stratified epithelium (Fig. 1 O and P). Expression of the to simplify analysis of estrogen effects. The vaginal epithelium of terminal differentiation marker, filaggrin (FLG), was absent in the both 8-wk-old OVX control and K5-Esr1KO mice was composed K5-Esr1KO mice (Fig. 1 Q and R). of two to three layers of cuboidal cells (Fig. 1 C and D). 17β- TRP63 is a crucial regulator of squamous differentiation and is Estradiol (E2) administration induced epithelial stratification no longer expressed once cells are committed to squamous epi- and full keratinization in control mice (Fig. 1E), whereas the K5- thelial lineages (18, 19). TRP63 was mainly expressed in the Esr1KO mice exhibited stratified epithelia, but not
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