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Thyroid Hormone Receptor Alpha Is Required for Thyroid Hormone-Dependent Neural Cell Proliferation During Tadpole Metamorphosis.

ABSTRACT: Thyroid hormone (T3) plays several key roles in development of the nervous system in vertebrates, controlling diverse processes such as neurogenesis, cell migration, apoptosis, differentiation, and maturation. In anuran amphibians, the hormone exerts its actions on the tadpole brain during metamorphosis, a developmental period dependent on T3. Thyroid hormone regulates gene transcription by binding to two nuclear receptors, TR? and TR?. Our previous findings using pharmacological and other approaches supported that TR? plays a pivotal role in mediating T3 actions on neural cell proliferation in Xenopus tadpole brain. Here we used Xenopus tropicalis (X. tropicalis) tadpoles with an inactivating mutation in the gene that encodes TR? to investigate roles for TR? in mitosis and gene regulation in tadpole brain. Gross morphological analysis showed that mutant tadpoles had proportionally smaller brains, corrected for body size, compared with wildtype, both during prometamorphosis and at the completion of metamorphosis. This was reflected in a large reduction in phosphorylated histone 3 (pH3; a mitosis marker) immunoreactive (ir) nuclei in prometamorphic tadpole brain, when T3-dependent cell proliferation is maximal. Treatment of wild type premetamorphic tadpoles with T3 for 48 h induced gross morphological changes in the brain, and strongly increased pH3-ir, but had no effect in mutant tadpoles. Thyroid hormone induction of the direct TR target genes thrb, klf9, and thibz was dysregulated in mutant tadpoles. Analysis of gene expression by RNA sequencing in the brain of premetamorphic tadpoles treated with or without T3 for 16 h showed that the TR? accounts for 95% of the gene regulation responses to T3.

SUBMITTER: Wen L

PROVIDER: S-EPMC6610206 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Thyroid Hormone Receptor Alpha Is Required for Thyroid Hormone-Dependent Neural Cell Proliferation During Tadpole Metamorphosis.

Wen Luan L He Cara C Sifuentes Christopher J CJ Denver Robert J RJ

Frontiers in endocrinology 20190628

Thyroid hormone (T<sub>3</sub>) plays several key roles in development of the nervous system in vertebrates, controlling diverse processes such as neurogenesis, cell migration, apoptosis, differentiation, and maturation. In anuran amphibians, the hormone exerts its actions on the tadpole brain during metamorphosis, a developmental period dependent on T<sub>3</sub>. Thyroid hormone regulates gene transcription by binding to two nuclear receptors, TRα and TRβ. Our previous findings using pharmacol ...[more]

PMID: 31316462

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Project description:BackgroundAnuran metamorphosis, which is obligatorily initiated and sustained by thyroid hormone (TH), is a dramatic example of extensive morphological, biochemical and cellular changes occurring during post-embryonic development. Thus, it provides an ideal model to understand the actions of the hormone and molecular mechanisms underlying these developmental and apoptotic processes. In addition to transcriptional factors, microRNAs (miRNAs) play key roles in diverse biological processes via post-transcriptional repression of mRNAs. However, the possible role of miRNAs in anuran metamorphosis is not well understood. Screening and identification of TH-responding miRNAs are required to reveal the integrated regulatory mechanisms of TH during metamorphosis. Given the specific role of TRs during M. fissipes metamorphosis and the characteristics of M. fissipes as an ideal model, Illumina sequencing technology was employed to get a full scope of miRNA in M. fissipes metamorphosis treated by T3.ResultsMorphological and histological analysis revealed that 24 h T3 treatment M. fissipes tadpoles resembled that at the climax of natural metamorphosis. Thus, small RNA libraries were constructed from control and 24 h T3 treatment groups. A total of 164 conserved miRNAs and 36 predicted novel miRNAs were characterized. Furthermore, 5' first and ninth nucleotides of miRNAs were significantly enriched in U in our study. In all, 21 miRNAs were differentially expressed between the T3 and control groups (p < 0.01). A total of 10,206 unigenes were identified as target genes of these differentially expressed miRNAs. KEGG pathway analysis indicated that the most overrepresented miRNA target genes were enriched in the "PI3k-Akt signaling pathway". In addition, a network associated with the TH signaling pathway provides an opportunity to further understand the complex biological processes that occur in metamorphosis.ConclusionsWe identified a large number of miRNAs during M. fissipes metamorphosis, and 21 of them were differentially expressed in the two groups that represented two different metamorphic stages. These miRNAs may play important roles during metamorphosis. The study gives us clues for further studies of the mechanisms of anuran metamorphosis and provides a model to study the mechanism of TH-affected biological processes in humans.

Project description:BackgroundChronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors.ObjectivesThe goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation.Methods and resultsHuman embryonic NT2 or rat pituitary GH3 cells were treated with 0.01-5 microM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element-luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element-luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1- 4.0 microM As.ConclusionsAs had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor-dependent processes by As is also potentially relevant to human developmental problems and disease risk.

Dataset Information

Thyroid Hormone Receptor Alpha Is Required for Thyroid Hormone-Dependent Neural Cell Proliferation During Tadpole Metamorphosis.

Publications

Thyroid Hormone Receptor Alpha Is Required for Thyroid Hormone-Dependent Neural Cell Proliferation During Tadpole Metamorphosis.

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