Claudin-3, claudin-7, and claudin-10 show different distribution patterns during decidualization and trophoblast invasion in mouse and human

Abstract

Implantation of the mammalian embryo requires profound endometrial changes for successful pregnancy, including epithelial-mesenchymal transition of the luminal epithelium and stromal-epithelial transition of the stromal cells resulting in decidualization. Claudins (Cldn) determine the variability in tight junction paracellular permeability and may play a role during these epithelial and decidual changes. We here localized Cldn3, Cldn7 and Cldn10 proteins in the different compartments of murine endometrium up to day 8.5 of pregnancy (dpc) as well as in human endometrium and first trimester decidua. In murine estrous endometrium, luminal and glandular epithelium exhibited Cldn3 and Cldn7, whereas Cldn10 was only detectable in glandular epithelium. At 4.5 dpc, Cldn3 protein shifted to an apical localization, whereas Cldn7 vanished in the epithelium of the implantation chamber. At this stage, there was no stromal signal for Cldn3 and Cldn7, but a strong induction of Cldn10 in the primary decidual zone. Cldn3 proteins emerged at 5.5 dpc spreading considerably from 6.5 dpc onward in the endothelial cells of the decidual blood sinusoids and in the decidual cells of the compact antimesometrial region. In addition to Cldn3, Cldn10 was identified in human endometrial epithelia. Both proteins were not detected in human first trimester decidual cells. Cldn3 was shown in murine trophoblast giant cells as well as in human extravillous trophoblast cells and thus may have an impact on trophoblast invasion in both species. We here showed a specific claudin signature during early decidualization pointing to a role in decidual angiogenesis and regulation of trophoblast invasion.

Direct Cell–Cell Interactions in the Endometrium and in Endometrial Pathophysiology

“…This is supported by the finding that besides claudin-1 also claudin-4 proteins increased from day 1 to day 6 pc in the luminal epithelium of the rat endometrium [66,67]. While claudin-3 revealed a consistent strong staining during this early phase of pregnancy both in glandular and luminal epithelial cells in the rat endometrium [67], it was shown in mice that the subcellular localization of claudin-3 and -7 switched from an apical and basal distribution to a strongly apically localization on day 4.5 pc in the luminal epithelium [52,68]. In contrast, high amounts of claudin-10 protein were present in the glandular epithelium in mice, but this claudin was absent in the luminal epithelium during the preimplantation period [68].…”

“…While claudin-3 revealed a consistent strong staining during this early phase of pregnancy both in glandular and luminal epithelial cells in the rat endometrium [67], it was shown in mice that the subcellular localization of claudin-3 and -7 switched from an apical and basal distribution to a strongly apically localization on day 4.5 pc in the luminal epithelium [52,68]. In contrast, high amounts of claudin-10 protein were present in the glandular epithelium in mice, but this claudin was absent in the luminal epithelium during the preimplantation period [68]. In these studies, however, it was not proven that these changes are dependent on the presence of a blastocyst.…”

“…Meanwhile, the tight junction proteins occludin, ZO-1, ZO-2 and claudin-1 were demonstrated to form associated complexes in these decidual cells of the primary decidual zone on day 6 pc, forming a barrier surrounding the embryo concurrently with the loss of the adjacent luminal epithelium [87]. Moreover, a strong induction of claudin-10 was observed in the primary decidual cells already on day 4.5 pc—thus, prior to trophoblast invasion—and expanded to the secondary decidua thereafter [68]. From 6.5 dpc onwards, additionally, an intense staining for the claudin-3 protein appeared in the cells of the secondary decidua [52,68], which was co-localized with the endothelial cell marker CD31 towards the mesometrial part of the implantation site [68].…”

“…Moreover, a strong induction of claudin-10 was observed in the primary decidual cells already on day 4.5 pc—thus, prior to trophoblast invasion—and expanded to the secondary decidua thereafter [68]. From 6.5 dpc onwards, additionally, an intense staining for the claudin-3 protein appeared in the cells of the secondary decidua [52,68], which was co-localized with the endothelial cell marker CD31 towards the mesometrial part of the implantation site [68]. Since Claudin-3 has been described as taking part in building up the blood-brain barrier in endothelia of the central nervous system [89], this protein distribution also could be involved in protecting the implantation site from immunoreactive substances originating from the maternal circulation.…”

Gain-of-function β-catenin in the uterine mesenchyme leads to impaired implantation and decidualization

“…Additionally, because β-catenin itself is a stimulator of proliferation it is possible that GOF β-catenin was capable of stimulating stromal cell proliferation even in the absence of pSTAT3-stimulated proliferation. Junctional complex proteins, such as occludins and claudins, have a tightly regulated spatio-temporal pattern of expression during implantation and decidualization, and remodeling of these complexes may lead to loss of epithelial apical-basal polarity allowing for blastocyst attachment to the LE (Thie et al 1996; Wang et al 2004; Pawar et al 2013; Schumann, et al 2015). It is also possible that dismantling of junctional complexes allows for breakdown of the LE at the implantation site to allow for blastocyst invasion.…”