Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and thyroid goiter. The thyroid disease typically develops around puberty and is associated with a mild organification defect, characterized by an inappropriate discharge of iodide upon perchlorate stimulation (a positive perchlorate discharge test). The gene (PDS) mutated in Pendred syndrome is expressed in thyroid and encodes a 780-amino acid protein (pendrin) that has recently been shown to function as an iodide/chloride transporter. We sought to establish the location of pendrin in the thyroid and to examine the regulatory network controlling its synthesis. Using peptide-specific antibodies for immunolocalization studies, pendrin was detected in a limited subset of cells within the thyroid follicles, exclusively at the apical membrane of the follicular epithelium. Interestingly, significantly greater amounts of pendrin were encountered in thyroid tissue from patients with Graves' disease. Using a cultured rat thyroid cell line (FRTL-5), PDS expression was found to be significantly induced by low concentrations of thyroglobulin (TG), but not by TSH, sodium iodide, or insulin. This is different from the established effect of TG, more typically a potent suppressor of thyroid-specific gene expression. Together, these results suggest that pendrin is an apical porter of iodide in the thyroid and that the expression and function of both the apical and basal iodide porters are coordinately regulated by follicular TG.

Thyroglobulin (TG), the primary synthetic product of the thyroid, is the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and degradation control thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (TSHR), increases thyroid hormone levels by upregulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of several thyroidspecific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex class I gene expression, which also is regulated by TTF-1 and Pax-8 in the thyroid, is decreased simultaneously. This helps maintain self-tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. In this report we show that follicular TG counter-regulates TSHincreased, thyroid-specific gene transcription by suppressing expression of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS, and TSHR genes, but increases class I expression. TG acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the 5 f lanking region of TTF-1. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS, and͞or TSHR gene expression. The inhibitory effect of TG on gene expression is not duplicated by thyroid hormones or iodide and may be mediated by a TG-binding protein on the apical membrane. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism that limits follicular function and contributes to follicular heterogeneity.