Expression of Na⁺/I⁻Symporter and Pendred Syndrome Genes in Trophoblast Cells¹

Abstract

Placental iodide transport is critical for the fetal thyroid function, but the molecular mechanisms of this transport are not understood. The expression of two recently identified iodide transporters, namely the sodium/iodide symporter (NIS) and pendrin, the product of the gene responsible for the Pendred syndrome (PDS), was studied using real-time kinetic quantitative PCR and immunohistochemistry 1) in placental tissues collected at different gestational ages and 2) in primary cultures of villous cytotrophoblast cells (VCT) that differentiate and fuse over 2-3 days in vitro to form villous syncytiotrophoblast (VSCT) cells. Both NIS and PDS genes are expressed in placenta, albeit at low levels compared with those in thyroid tissue. NIS gene expression in placental samples from first trimester and term pregnancies was similar. In contrast, the expression of PDS gene was higher in term than in first trimester pregnancy samples. In vitro, NIS gene was expressed at a high level in VCT obtained from first trimester pregnancy, and its expression decreased by 3- to 4-fold during the differentiation of VCT in VSCT. Expression of NIS was lower (up to 30-fold) in VCT obtained in placental samples from third trimester than from first trimester pregnancy. In contrast, the expression of PDS gene was low in VCT and increased by 5- to 10-fold during VSCT formation; this was observed in cells isolated from placental samples of both first trimester and term pregnancies. Immunohistochemical analysis showed that NIS protein was present on the entire membrane of VCT, whereas pendrin was mainly located at the brush border membrane of VSCT, facing the mother. In conclusion, 1) NIS and PDS genes are differently expressed in the placenta during gestation; and 2) whereas pendrin is expressed at the brush border membrane of syncytiotrophoblast cells, NIS protein is mainly located in the cytotrophoblast layer.

Pathogenetics of the Human SLC26 Transporters

“…The 5 kb SLC26A4 transcript encodes a 780 amino acid protein, designated pendrin, which is predicted to contain 11 putative TMD [54]. Pendrin is expressed primarily in the thyroid gland and inner ear, with weaker signals in the kidney, brain, mammary gland, endometrium and placenta [54][55][56], and it shares significant amino acid identities with sulfate transporters, including SLC26A1 (SAT-1) (30%), SLC26A2 (DTDST) (30%) and SLC26A3 (DRA) (44%) [54]. However, despite these amino acid similarities, pendrin was unable to induce any sulfate transport in Xenopus oocytes or Sf9 insect cells [57,58].…”

Expression, Regulation, and Function of Paired-Box Gene 8 in the Human Placenta and Placental Cancer Cell Lines

“…The experiments described above clearly demonstrated that PAX8 is expressed in JAR cells and that this expression is regulated by hCG. To identify the effects of this expression, we overexpressed PAX8 in JAR cells by means of transfection and performed quantitative RT-PCR to measure the levels of mRNA for the two PAX8-target genes, WT1 (25, 26) and NIS (10), both of which are known to be expressed in human placenta (4,17,27). As shown in Fig.…”

“…Recent reports suggest that PAX8 is also involved in modulating the expression of D2 deiodinase (15,16), one of the enzymes responsible for the deiodination of iodothyronines. More recent evidence indicates that the NIS (17) and the iodothyronine deiodinases, D2 and D3, which were originally considered to be thyroid specific, are also expressed by placental trophoblasts (18,19), in which their presence is essential for ensuring adequate supplies of iodide for the synthesis of fetal thyroid hormones. These discoveries suggested that placental expression levels of these genes might be modulated by PAX8, as they are in the thyroid.…”

Interleukin-4 Induces CpG Site-Specific Demethylation of the Pendrin Promoter in Primary Human Bronchial Epithelial Cells

“…In these tissues, it is involved in iodide flux into the thyrocyte follicular lumen, maintenance of the pH, ion composition and volume of the endolymph, and moreover body acid-base equilibrium, fluid homeostasis and blood pressure regulation. Pendrin is also expressed, although at a minor level relative to the aforementioned tissues, in the placenta [9], lactating mammalian glands [10], testis [11], prostate [11], endometrium [12], platelets [13], and lung [14]. …”