Dataset Information

Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance.

ABSTRACT:

Background

Proper thyroid hormone signaling via the TRα1 nuclear receptor is required for normal neurodevelopmental processes. The specific downstream mechanisms mediated by TRα1 that impact brain development remain to be investigated.

Methods

In this study, the structure, function and transcriptome of hippocampal tissue in a mouse model expressing the first RTHα mutation discovered in a patient, THRA E403X, were analyzed. RNAscope was used to visualize the spatial and temporal expression of Thra1 mRNA in the hippocampus of WT mice, which is corresponding to THRA1 mRNA in humans. The morphological structure was analyzed by Nissl staining, and the synaptic transmission was analyzed on the basis of long-term potentiation. The Morris water maze test and the zero maze test were used to evaluate the behavior. RNA-seq and quantitative real-time PCR were used to analyze the differentially expressed genes (DEGs) of the hippocampal tissues in the mouse model expressing the Thra E403X mutation.

Results

The juvenile mutant Thra E403X mice presented with delayed neuronal migration, disordered neuronal distribution, and decreased synaptic plasticity. A total of 754 DEGs, including 361 upregulated genes and 393 downregulated genes, were identified by RNA-seq. DEG-enriched Gene Ontology (GO) and KEGG pathways were associated with PI3K-Akt signaling, ECM-receptor interaction, neuroactive ligand-receptor interaction, and a range of immune-related pathways. 25 DEGs were validated by qPCR.

Conclusions

The ThraE403X mutation results in histological and functional abnormalities, as well as transcriptomic alterations in the juvenile mouse hippocampus. This study of the ThraE403X mutant offers new insights into the biological cause of RTHα-associated neurological diseases.

SUBMITTER: Fang Y

PROVIDER: S-EPMC9066571 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance.

Fang Yingxin Y Dang Pingping P Liang Yue Y Zhao Defa D Wang Ranran R Xi Yue Y Zhang Dan D Wang Wei W Shan Zhongyan Z Teng Weiping W Teng Xiaochun X

European thyroid journal 20220415 2

<h4>Background</h4>Proper thyroid hormone signaling via the TRα1 nuclear receptor is required for normal neurodevelopmental processes. The specific downstream mechanisms mediated by TRα1 that impact brain development remain to be investigated.<h4>Methods</h4>In this study, the structure, function and transcriptome of hippocampal tissue in a mouse model expressing the first RTHα mutation discovered in a patient, THRA E403X, were analyzed. RNAscope was used to visualize the spatial and temporal ex ...[more]

PMID: 35262510

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Project description:Disruption of thyroid hormone signalling can alter growth, development and energy metabolism. Thyroid hormones exert their effects through interactions with thyroid receptors that directly bind thyroid response elements and can alter transcriptional activity of target genes. The effects of short-term thyroid hormone perturbation on hepatic mRNA transcription in juvenile mice were evaluated, with the goal of identifying genes containing active thyroid response elements. Thyroid hormone disruption was induced from postnatal day 12 to 15 by adding goitrogens to dams' drinking water (hypothyroid). A subgroup of thyroid hormone-disrupted pups received intraperitoneal injections of replacement thyroid hormones four hours prior to sacrifice (replacement). An additional group received only thyroid hormones four hours prior to sacrifice (hyperthyroid). Hepatic mRNA was extracted and hybridized to Agilent mouse microarrays.Transcriptional profiling enabled the identification of 28 genes that appeared to be under direct thyroid hormone-regulation. The regulatory regions of the genome adjacent to these genes were examined for half-site sequences that resemble known thyroid response elements. A bioinformatics search identified 33 thyroid response elements in the promoter regions of 13 different genes thought to be directly regulated by thyroid hormones. Thyroid response elements found in the promoter regions of Tor1a, 2310003H01Rik, Hect3d and Slc25a45 were further validated by confirming that the thyroid receptor is associated with these sequences in vivo and that it can bind directly to these sequences in vitro. Three different arrangements of thyroid response elements were identified. Some of these thyroid response elements were located far up-stream (> 7 kb) of the transcription start site of the regulated gene.Transcriptional profiling of thyroid hormone disrupted animals coupled with a novel bioinformatics search revealed new thyroid response elements associated with genes previously unknown to be responsive to thyroid hormone. The work provides insight into thyroid response element sequence motif characteristics.

Dataset Information

Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance.

Background

Methods

Results

Conclusions

Publications

Histological, functional and transcriptomic alterations in the juvenile hippocampus in a mouse model of thyroid hormone resistance.

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