Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation
Hong Soon Kang, … , Raja Jothi, Anton M. Jetten
Hong Soon Kang, … , Raja Jothi, Anton M. Jetten
Published October 30, 2017
Citation Information: J Clin Invest. 2017;127(12):e94417. https://doi.org/10.1172/JCI94417.
View: Text | PDF
Research Article Endocrinology

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

  • Text
  • PDF
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

×

Figure 6

GLIS3 regulates the transcription of a subset of differentially expressed genes directly through its interaction with GLIS3-BS.

Options: View larger image (or click on image) Download as PowerPoint
GLIS3 regulates the transcription of a subset of differentially expresse...
(A) Pie chart showing the position of GLIS3-binding regions on the genome of the mouse thyroid gland relative to their nearest gene identified by Chipset analysis. The promoter is defined as the region up to 5 kb upstream of the TSS. (B) De novo consensus motif analysis using MEME program identified a G-rich GLIS3-binding motif, which is similar to GLIS3-BS identified previously by an in vitro binding assay. (C) GLIS3-EGFP occupancy on genome loci of several GLIS3-regulated genes associated with TH biosynthesis or cell proliferation. Tshr and Ccnb1 are included as negative controls. Gene tracks were taken from the UCSC Genome Browser (https://genome.ucsc.edu/). For each locus, Chipset analyses of input chromatin (Input) chromatin pulled down with GFP-BP-agarose (GFP-ChIP) from GLIS3-EGFP and WT thyroid glands are shown as indicated. GLIS3-binding peaks were observed only in IP GFP. (D) Schematic view of the key regulatory functions of GLIS3 in thyroid follicular cells. TSH/TSHR activates several kinase pathways that subsequently lead to increased transcription of many genes required for TH biosynthesis. GLIS3 is essential for TH biosynthesis, acting by directly regulating the transcription of several key TH biosynthetic genes, particularly Pds and Nis. Prolonged elevated levels of TSH induce thyroid follicular cell proliferation and goiter development through AKT1-independent activation of the mTORC1 signaling pathway. GLIS3 is required for the activation of the mTORC1 pathway and thyroid follicular cell proliferation. GLIS3 is critical in mediating the downstream actions of TSH/TSHR. GLIS3 activity might be controlled by TSH/TSHR and regulated by one of the TSH/TSHR-activated kinase pathways.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts