GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation
Hong Soon Kang, Dhirendra Kumar, Grace Liao, Kristin Lichti-Kaiser, Kevin Gerrish, Xiao-Hui Liao, Samuel Refetoff, Raja Jothi, Anton M. Jetten
Hong Soon Kang, Dhirendra Kumar, Grace Liao, Kristin Lichti-Kaiser, Kevin Gerrish, Xiao-Hui Liao, Samuel Refetoff, Raja Jothi, Anton M. Jetten
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Research Article Endocrinology

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Abstract

Deficiency in Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and the mechanism by which GLIS3 dysfunction causes hypothyroidism are unknown. In the current study, we demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone. Using ChIP-Seq and promoter analysis, we demonstrate that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters. The repression of cell proliferation of GLIS3-deficient thyroid follicular cells was due to the inhibition of TSH-mediated activation of the mTOR complex 1/ribosomal protein S6 (mTORC1/RPS6) pathway as well as the reduced expression of several cell division–related genes regulated directly by GLIS3. Consequently, GLIS3 deficiency in a murine model prevented the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells and uncovers a mechanism by which GLIS3 deficiency causes neonatal hypothyroidism and prevents goiter development.

Authors

Hong Soon Kang, Dhirendra Kumar, Grace Liao, Kristin Lichti-Kaiser, Kevin Gerrish, Xiao-Hui Liao, Samuel Refetoff, Raja Jothi, Anton M. Jetten

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Figure 3

Proliferation of thyroid follicular cells was greatly reduced in KO-LID mice.

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Proliferation of thyroid follicular cells was greatly reduced in KO-LID ...
(A) EdU incorporation was analyzed in the thyroid of 3-week-old WT and Glis3KO mice and WT-LID and KO-LID mice as described in Methods. Arrows indicate PAX8+EdU+ cells, and arrowheads indicate PAX8–EdU+ cells. Scale bar: 50 μm. (B) Percentages of PAX8+ cells staining EdU+ were calculated and plotted. n ≥ 3 for each group. (C) Heatmaps generated from gene expression profiles obtained by microarray analyses of thyroid glands from WT and Glis3KO mice fed either ND or LID as indicated. The same genes associated with cell cycle, TH biosynthesis, ECM, and cytokine/chemokine pathways as shown in Supplemental Table 3 are clustered as indicated. (D) QRT-PCR analysis of the expression of several cell proliferation regulatory genes in WT and Glis3KO mice fed with ND or LID. n ≥ 4. Data are shown as mean ± SEM. *P < 0.05; **P < 0.001; ***P < 0.0001, Student’s t test.