Endocrine Abstracts

Background: Most thyroid specific genes are transcriptionally regulated by TSH-TSHR signalling and T4-driven negative feedback of TSH secretion at the pituitary. However, local autoregulation of transcription has been described from IGF-IGFR, follicular thyroglobulin, or iodine. We aimed to investigate the TSH dependency of thyroid transcriptional regulation in the Dehal1 knockout, devoid of iodide-recycling capacity from iodotyrosines.

Methods: Dehal1 knockout (KO) and wild-type (WT) mice were fed with a diet containing high iodine (5.6 µg/l/day, to secure iodine sufficiency) for 28 days. Plasma TSH and T4 were determined on days 0 and 28 by radioimmunoassay and LC/MS-MS, respectively. After sacrifice, RNA from thyroids were isolated and cDNA-qPCR were used to determine expression levels of genes involved in basal/apical iodide transport (Slc5a5, Slc26a4, Slc26a7), nuclear transcription (Pax8, Nkx2-1, Foxe1, Glis3) and thyroid hormone synthesis and secretion (Tshr, Tg, Tpo, Duox2, Duox2, Dehal1, Slc16a2, Dio1).

Results: Under sufficient iodine, TSH was equal in both genotypes (logTSH: 1.45 ± 0.1 vs 1.45 ± 0.4 mU/l, P > 0.05). Plasma T4 (58.5 vs 59.9 ng/ml) and T3 (0.5 vs 0.47 ng/ml) were normal in both genotypes respectively (P > 0.05). However, despite complete euthyroidism, Dehal1-KO mice showed a dramatic increase of overall gene expression at baseline, as compared to WT mice (mean 8.7-fold upregulation, 14 genes studied) including hormone-synthetic Tshr (8.7-fold), Tg (10.2), Tpo (5.8), Duox2 (8.4), Duoxa2 (4.5), Slc16a2 (8.2) and transcriptional factors Nkx2-1 (6.4), Pax8 (28), Foxe1 (7.5) and Glis3 (11). Interestingly, basal and apical iodide transporters showed opposite modulation: Slc5a5 (Nis) was maximally overexpressed in KO mice (20-fold) while expression of apical Slc26a4 and Slc26a7, exceptionally, remained unchanged.

Conclusion: A TSH-independent mechanism of transcriptional regulation is active in the thyroid glands of Dehal1 knockout mice, which are fully euthyroid. This mechanism is not indiscriminate but gene-specific, since apical iodide transporters pendrin and Slc26a7 are preserved from regulation. Our data suggest that intrathyroidal, yet unspecified signals, may regulate specific gene expression to compensate for the deficient iodide recycling before hypothyroidism occurs.