Dataset Information

Thyroid Hormone Receptor Alpha Mutations Lead to Epithelial Defects in the Adult Intestine in a Mouse Model of Resistance to Thyroid Hormone.

ABSTRACT:

Background

The thyroid hormone triiodothyronine (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. The discovery of patients with resistance to thyroid hormone (RTH?) >50 years ago and subsequent identification of genetic mutations in only the THRB gene in these patients suggest that mutations in the THRA gene may have different pathological manifestations in humans. Indeed, the recent discovery of a number of human patients carrying heterozygous mutations in the THRA gene (RTH?) revealed a distinct phenotype that was not observed in RTH patients with THRB gene mutations (RTH?). That is, RTH? patients have constipation, implicating intestinal defects caused by THRA gene mutations.

Methods

To determine how TR?1 mutations affect the intestine, this study analyzed a mutant mouse expressing a strong dominantly negative TR?1 mutant (denoted TR?1PV; Thra1^PV mice). This mutant mouse faithfully reproduces RTH? phenotypes observed in patients.

Results

In adult Thra1^PV/+ mice, constipation was observed just like in patients with TR? mutations. Importantly, significant intestinal defects were discovered, including shorter villi and increased differentiated cells in the crypt, accompanied by reduced stem-cell proliferation in the intestine.

Conclusions

The findings suggest that further analysis of this mouse model should help to reveal the molecular and physiological defects in the intestine caused by TR? mutations and to determine the underlying mechanisms.

SUBMITTER: Bao L

PROVIDER: S-EPMC6437623 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Thyroid Hormone Receptor Alpha Mutations Lead to Epithelial Defects in the Adult Intestine in a Mouse Model of Resistance to Thyroid Hormone.

Bao Lingyu L Roediger Julia J Park Sunmi S Fu Liezhen L Shi Bingyin B Cheng Sheue-Yann SY Shi Yun-Bo YB

Thyroid : official journal of the American Thyroid Association 20190125 3

<h4>Background</h4>The thyroid hormone triiodothyronine (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. The discovery of patients with resistance to thyroid hormone (RTHβ) >50 years ago and subsequent identification of genetic mutations in only the THRB gene in these patients suggest that mutations in the THRA gene may have different patho ...[more]

PMID: 30595106

Similar Datasets

Project description:Background: Mutations of thyroid hormone receptor α1 (TRα1) cause resistance to thyroid hormone (RTHα). Patients exhibit growth retardation, delayed bone development, anemia, and bradycardia. By using mouse models of RTHα, much has been learned about the molecular actions of TRα1 mutants that underlie these abnormalities in adults. Using zebrafish models of RTHα that we have recently created, we aimed to understand how TRα1 mutants affect the heart function during this period. Methods: In contrast to human and mice, the thra gene is duplicated, thraa and thrab, in zebrafish. Using CRISPR/Cas9-mediated targeted mutagenesis, we created C-terminal mutations in each of two duplicated thra genes in zebrafish (thraa 8-bp insertion or thrab 1-bp insertion mutations). We recently showed that these mutant fish faithfully recapitulated growth retardation as found in patients and thra mutant mice. In the present study, we used histological analysis, gene expression profiles, confocal fluorescence, and transmission electron microscopy (TEM) to comprehensively analyze the phenotypic characteristics of mutant fish heart during development. Results: We found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and the decreased circulating blood speed and reduced expression of contractile genes indicated weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days postfertilization (juveniles). Furthermore, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by TEM, suggesting that the abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish. Conclusions: Using a zebrafish model of RTHα, the present study demonstrated for the first time that TRα1 mutants could act to cause abnormal heart structure, weaken contractility, and disrupt sarcomere organization that affect heart functions. These findings provide new insights into the bradycardia found in RTHα patients.

Dataset Information

Thyroid Hormone Receptor Alpha Mutations Lead to Epithelial Defects in the Adult Intestine in a Mouse Model of Resistance to Thyroid Hormone.

Background

Methods

Results

Conclusions

Publications

Thyroid Hormone Receptor Alpha Mutations Lead to Epithelial Defects in the Adult Intestine in a Mouse Model of Resistance to Thyroid Hormone.

Similar Datasets

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