Abstract

Thyroid hormone (T3) is critical for vertebrate development and affects the function of many adult tissues and organs. Its genomic effects are mediated by thyroid hormone nuclear receptors (TRs) present in all vertebrates. Recent discovery of human patients carrying heterozygous mutations in the THRA gene (RTHalpha) revealed a distinct phenotype that was not observed in the RTH patients with THRB gene mutations (RTHbeta). That is, the RTHalpha patients have constipation, implicating intestinal defects caused by THRA gene mutations. To determine how TRalpha1 mutations affect the intestine, we have analyzed the histology of intestine in TRalpha1PV mice. We found that adult TRalpha1PV/+ mice exhibit constipation just like in patients with TRalpha mutations. Importantly, we discovered significant intestinal defects, including shorter villi, increased differentiated cells in the crypt, accompanied by reduced stem cell proliferation in the intestine. Our findings suggest that further analysis of this mouse model should help reveal the molecular and physiological defects in the intestine caused by TRalpha mutations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC008752-39
Application #
10014305
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
39
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

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Han, Cho Rong; Park, Sunmi; Cheng, Sheue-Yann (2017) NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor ?1. Sci Rep 7:18080
Milanesi, Anna; Lee, Jang-Won; Yang, An et al. (2017) Thyroid Hormone Receptor Alpha is Essential to Maintain the Satellite Cell Niche During Skeletal Muscle Injury and Sarcopenia of Aging. Thyroid 27:1316-1322
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Jang, Jeon Yeob; Choi, Sung Yong; Park, Intae et al. (2017) VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis. EMBO Mol Med 9:750-769
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Park, Jeong Won; Zhao, Li; Willingham, Mark C et al. (2016) Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor ?. Mol Carcinog :
Sayre, Naomi L; Sifuentes, Mikaela; Holstein, Deborah et al. (2016) Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage. J Cereb Blood Flow Metab :

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