Thyroid Hormone Nuclear Receptors in Health and Disease

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

1.TRalpha1 mutants cause morphological and functional defects in mouse model of RTHalpha (Thra1PV/+ mice): We used histopathological analysis, confocal fluorescence imaging, transmission electron microscopy (TEM), and gene expression profiles to comprehensively analyze the colonic abnormalities of Thra1PV/+ mouse. We found a significant increase in colonic transit time and decrease stool water content in Thra1PV/+ mouse, mimicking constipation as found in patients. TEM analysis revealed shorter muscle fibers with wider gap junctions between muscle cells, fewer caveolae, and hypoplastic interstitial cells of Cajal (ICC) in the rectal smooth muscles of Thra1PV/+ mice. These abnormal histological manifestations suggested defective intercellular transfer of small molecules, electrolytes, and signals for communication among muscles cells, validated by Lucifer Yellow transferring assays. Expression of key smooth muscle contractility regulators, such as calmodulin, myosin light-chain kinase, and phosphorylated myosin light chain, was markedly lower, and c-KIT signaling in ICC was attenuated, resulting in decreased contractility of the rectal smooth muscles of Thra1PV/+ mice. Collectively, these abnormal histopathological alterations and diminished contractility regulators led to the constipation exhibited in patients. This is the first demonstration that TRalpha mutants could act to cause abnormal rectum smooth muscle organization, defects in intercellular exchange of small molecules, and decreased expression of contractility regulators to weaken the contractility of rectal smooth muscles. These findings provide new insights into the molecular basis underlying constipation found in RTHalpha patients. These findings have been published in Thyroid (Kim et.al., 2023). 2.Defining the role of TRalpha mutants in uterus functions. Using Thra1PV/+ mice, we found degenerated uterus with fibrosis in the mutant mice. The mutant uterus was atrophied with decreased proliferation, increased apoptosis and reduction in the number of glands. RNA-seq analysis of the uterus showed major alterations in lymphocyte functions and signaling. RNA-seq analysis revealed IL-33 was highly elevated, subsequently validated by RT/qPCR and western blot analysis. Immunohistochemical analysis showed that IL-33 was highly over-expressed in the epithelial cells. The findings that TRalpha mutants could cause degenerated uterus has broadened the scope of the biological impact of mutant actions. Elucidation of how TRalpha mutants cause uterus abnormalities will pave the way for further understanding of the important role of TRalpha in female reproduction biology.