Differential Expression of Ezrin and CLP36 in the Two Layers of Syncytiotrophoblast in Rats

Abstract

The syncytiotrophoblast in the placenta serves as an interface for efficient maternal-fetal exchange of nutrients, metabolites and xenobiotic compounds, and membrane transport processes play pivotal roles in efficient uptake of certain compounds and in exclusion of others; this is referred to as the blood-placenta barrier. 1,2) In humans, the syncytiotrophoblast is derived from cell fusion of the progenitor cytotrophoblast and consists a polar single epithelium. The apical and basal plasma membranes of the syncytiotrophoblast face the maternal blood and the endothelial cells of the fetal blood vessels, respectively. Specific localization of transporters in the apical and the basal plasma membranes of the syncytiotrophoblast is important for plancental function in terms of vectorial transport of substrates. For example, ATP-binding cassette transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein, are localized in the apical membrane of the syncytiotrophoblast, where they restrict the entry of xenobiotics, including digoxin, saquinavir, vinblastine, topotecan and mitoxantrone.3) On the other hand, organic anion transporting polypeptide 2B1 is localized in the basal membrane of the syncytiotrophoblast and mediates uptake of dehydroepiandrosterone sulphate from fetal blood to placenta. 4)The postsynaptic density 95 (PSD-95)/Discs-large/zonula occludens-1 (ZO-1) (PDZ) domain-containing scaffold proteins, such as PDZ domain containing 1 (PDZK1) and Na ϩ /H ϩ exchanger regulatory factor 1 (NHERF1) , play a role in the association and functional regulation of organic anion transporters in the apical membranes of the renal proximal epithelial cells.5) It has also been reported that PDZK1 functions as a regulator for oligopeptide transporter (PEPT) 2 and organic cation/carnitine transporter 2, through direct interaction with their C-termini. 6,7) However, the mechanisms that control the polar distribution of proteins in the syncytiotrophoblast are still unclear.In mouse and rat, however, the labyrinthine part of the placenta is the principal site of maternal-fetal exchange. The labyrinthine wall, which lies between the maternal blood space and fetal vessels, is composed of three trophoblast layers, 1,[8][9][10] i.e., the porous cytotrophoblast layer, and the maternal-side and fetal-side syncytiotrophoblast layers (also called SynI and SynII, respectively). It is suggested that connexin 26 gap-junctional channels and transporters allow diffusion of nutrients between the two syncytiotrophoblast layers.11-13) Therefore, it is considered that the apical membrane of SynI and the basal membrane of SynII correspond to the apical and basal membranes of human syncytiotrophoblast, respectively, although the physiological role of the double epithelial layers, in contrast to the single epithelial cell layer in humans, remains unclear.We established conditionally immortalized rat syncytiotrophoblast cell lines, TR-TBT 18d-1 and TR-TBT 18d-2 from The syncytiotrophoblast, which regulates maternal-fetal transfer ...

Fetal Growth Retardation and Lack of Hypotaurine in Ezrin Knockout Mice

“…Ezrin was primarily expressed in the labyrinth zone of placenta (Figure 1B), and was predominantly localized at the apical membrane of syncytiotrophoblast in placenta of Ez +/+ fetal mice (Figure 1B), in accordance with previous observations in rat placenta [14]. Intrauterine growth retardation was observed at gestational day 15.5 and later in Ez −/− mice (Figure 3).…”

“…Recent studies indicate that the functional expression of some apical membrane transporters such as cystic fibrosis transmembrane conductance regulator (CFTR) and Na + /H + exchanger (NHE3) is regulated by their interaction with ezrin in the kidney and respiratory tract [9]–[11]. Ezrin is the most abundant of the ERM proteins and is specifically associated with the apical membrane of syncytiotrophoblast [12]–[14]. Thus, transporter/ezrin complexes are considered to be important for the proper transport of physiological nutrients and metabolites in syncytiotrophoblast.…”

Contribution of Ezrin on the Cell Surface Plasma Membrane Localization of Programmed Cell Death Ligand-1 in Human Choriocarcinoma JEG-3 Cells

“…Although there is a lack of data on in vitro cell lines derived from human gestational trophoblastic tumors, several histopathological studies have demonstrated the strong expression of PD-L1 in the plasma membrane of tumor cells obtained from human gestational trophoblastic neoplasia [ 10 , 12 , 13 ]. In addition, Higuchi et al immunohistochemically identified that ezrin is highly localized in the apical membranes of a syncytiotrophoblast cell line, which is a source of GTN derived from rat placenta [ 43 ]. Taken together, these findings suggest that PD-L1, ezrin, and radixin, but not moesin, are highly expressed at the genetic and protein levels in JEG-3 cells, and that PD-L1 is co-localized with ezrin and radixin in the plasma membrane of this cell line.…”

6-Mercaptopurine Transport by Equilibrative Nucleoside Transporters in Conditionally Immortalized Rat Syncytiotrophoblast Cell Lines TR-TBTs

“…The TR‐TBTs were established by Kitano et al14 The cells exhibited typical characteristics of in vivo syncytiotrophoblast 14. Especially, they were testified to form a polarized layer of cells, with the apical and basolateral membranes having functional similarities to those in rat placenta 14,17. In addition, TR‐TBTs express many transporter genes found in the human placenta and also exhibit the uptake activity of taurine and gamma‐aminobutyric acid through several transporters 6.…”

“…5). It is known that the syncytiotrophoblast of rat is composed of two layers, SynI (maternal‐side) and SynII (fetal‐side) 17. TR‐TBT 18d‐1 and TR‐TBT 18d‐2 are derived from SynI and SynII in rat, respectively 14.…”