Thyroid transcription factors (TTFs) - NKX2-1, FOXE1, PAX8 and HHEX - regulate multiple genes involved in thyroid development in mice but little is known about TTF regulation of thyroid-specific genes - thyroglobulin (TG), thyroid peroxidase (TPO), deiodinase type 2 (DIO2), sodium/iodide symporter (NIS) and TSH receptor (TSHR) - in adult, human thyrocytes. Thyrotropin (thyroid-stimulating hormone, TSH) regulation of thyroid-specific gene expression in primary cultures of human thyrocytes is biphasic yielding an inverted U-shaped dose-response curve (IUDRC) with upregulation at low doses and decreases at high doses. Herein we show that NKX2-1, FOXE1 and PAX8 are required for TSH-induced upregulation of the mRNA levels of TG, TPO, DIO2, NIS, and TSHR whereas HHEX has little effect on the levels of these thyroid-specific gene mRNAs. We show that TSH-induced upregulation is mediated by changes in their transcription and not by changes in the degradation of their mRNAs. In contrast to the IUDRC of thyroid-specific genes, TSH effects on the levels of the mRNAs for NKX2-1, FOXE1 and PAX8 exhibit monophasic decreases at high doses of TSH whereas TSH regulation of HHEX mRNA levels exhibits an IUDRC that overlaps the IUDRC of thyroid-specific genes. In contrast to findings during mouse development, TTFs do not have major effects on the levels of other TTF mRNAs in adult, human thyrocytes. Thus, we found similarities and important differences in the regulation of thyroid-specific genes in mouse development and TSH regulation of these genes in adult, human thyrocytes.

甲状腺转录因子 (TTF) - NKX2-1、FOXE1、PAX8 和 HHEX - 调节小鼠甲状腺发育中涉及的多个基因，但人们对 TTF 对甲状腺特异性基因 - 甲状腺球蛋白 (TG)、甲状腺过氧化物酶 (TPO)、 2 型脱碘酶 (DIO2)、钠/碘同向转运体 (NIS) 和 TSH 受体 (TSHR) - 存在于成人、人类甲状腺细胞中。促甲状腺素（促甲状腺激素，TSH）对人甲状腺细胞原代培养物中甲状腺特异性基因表达的调节是双相的，产生倒U形剂量反应曲线（IUDRC），低剂量时上调，高剂量时下调。在此我们表明，NKX2-1、FOXE1 和 PAX8 是 TSH 诱导的 TG、TPO、DIO2、NIS 和 TSHR mRNA 水平上调所必需的，而 HHEX 对这些甲状腺特异性基因 mRNA 的水平几乎没有影响。我们发现 TSH 诱导的上调是通过其转录变化介导的，而不是通过其 mRNA 降解的变化介导的。与甲状腺特异性基因的 IUDRC 相反，TSH 对 NKX2-1、FOXE1 和 PAX8 mRNA 水平的影响在高剂量 TSH 下表现出单相降低，而 TSH 对 HHEX mRNA 水平的调节表现出 IUDRC 与甲状腺特异性基因。与小鼠发育过程中的发现相反，TTF 对成年人类甲状腺细胞中其他 TTF mRNA 的水平没有重大影响。因此，我们发现小鼠发育中甲状腺特异性基因的调节与成人、人类甲状腺细胞中这些基因的 TSH 调节存在相似性和重要差异。