The overall goal of this proposal is to gain a better understanding of the central regulation of the hypothalamic- pituitary-thyroid axis (HPT axis) by thyroid hormones (T4 and T3) and thyrotropin-releasing hormone (TRH). Thyroid stimulating hormone (TSH also known as thyrotropin) is a heterodimeric protein, which is synthesized and secreted from the thyrotroph and is essential for activating thyroid hormone (TH) synthesis in the thyroid. THRB isoforms (principally the THRB2 isoform) mediates T3 negative feedback at the level of the hypothalamus and pituitary thyrotroph based on elevated TH and TSH levels in THRB isoform KO mice. In contrast, THRA1 KO mice actually display slightly reduced TH levels associated with slightly elevated TSH levels. These findings suggest that THRA1 has no role in negative T3 regulation of the HPT axis in the euthyroid state. However, THRA1 must play some role since KO of all THR isoforms (THRA1, THRB1 and THRB2) markedly elevates both TSH and TH levels above those observed in THRB KO mice. What explains this THR isoform difference? We hypothesize that THRB isoforms bind preferentially to a negative thyroid response element(s) (nTREs) in the Tshb gene to mediate negative T3 regulation. In the absence of T3, other workers have suggested that TRH and TSH production are maximal, and that the unliganded THRs play no direct role in activating the axis. Our in vitro studies and studies in KO mice challenge this model. We have demonstrated, for example, that the N-terminus of THRB2 contains a potent trans-activation domain and that both THRB2 and hypothalamic TRH are necessary for full activation of Tsh subunit gene expression in the hypothyroid state in vivo. We hypothesize that specific THR isoforms mediate an increase in histone acetylation on the Tshb gene, which underlies the mechanism by which the unliganded THRB2 activates basal gene expression. Finally, we have characterized a unique, permanent mouse thyrotroph cell line (T?T1.1) that displays physiological T3 negative regulation of the Tshb gene. We find that acute changes in histone methylation of the proximal Tshb gene occur after T3 treatment. We hypothesize that liganded THRs recruit a histone demethylase to Tshb resulting in a decrease in histone methylation and T3- inhibition of gene expression.

Public Health Relevance

The overall goal of this proposal is to gain a better understanding of how thyroid hormone production is regulated by pituitary thyrotropin (TSH) and hypothalamic thyrotropin-releasing hormone (TRH). Understanding how genes are regulated by thyroid hormones will elucidate mechanisms responsible for development, growth and metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Pinto, Vitor M S; Minakhina, Svetlana; Qiu, Shuiqing et al. (2017) Naturally Occurring Amino Acids in Helix 10 of the Thyroid Hormone Receptor Mediate Isoform-Specific TH Gene Regulation. Endocrinology 158:3067-3078
Wondisford, Fredric E (2015) A direct role for thyroid hormone in development of the adrenal cortex. Endocrinology 156:1939-40
Aninye, Irene O; Matsumoto, Shunichi; Sidhaye, Aniket R et al. (2014) Circadian regulation of Tshb gene expression by Rev-Erb? (NR1D1) and nuclear corepressor 1 (NCOR1). J Biol Chem 289:17070-7
Ortiga-Carvalho, Tânia M; Sidhaye, Aniket R; Wondisford, Fredric E (2014) Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol 10:582-91
Paik, Elizabeth J; Mahony, Shaun; White, Richard M et al. (2013) A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis. Stem Cell Reports 1:425-36
Chiamolera, Maria I; Sidhaye, Aniket R; Matsumoto, Shunichi et al. (2012) Fundamentally distinct roles of thyroid hormone receptor isoforms in a thyrotroph cell line are due to differential DNA binding. Mol Endocrinol 26:926-39
Costa-e-Sousa, Ricardo H; Astapova, Inna; Ye, Felix et al. (2012) The thyroid axis is regulated by NCoR1 via its actions in the pituitary. Endocrinology 153:5049-57
Wondisford, Fredric E (2011) A new medical therapy for Cushing disease? J Clin Invest 121:4621-3
Richter, Claus-Peter; Munscher, Adrian; Machado, Danielle Santana et al. (2011) Complete activation of thyroid hormone receptor ýý by T3 is essential for normal cochlear function and morphology in mice. Cell Physiol Biochem 28:997-1008
Machado, Danielle S; Sabet, Amin; Santiago, Leticia A et al. (2009) A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo. Proc Natl Acad Sci U S A 106:9441-6

Showing the most recent 10 out of 29 publications