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Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis.

ABSTRACT: Amphibian metamorphosis serves as an excellent model to study T3 function during postembryonic development in vertebrate due to its total dependence on T3. Earlier molecular studies in the model species Xenopus laevis have led to a number of important in vivo findings on the function and mechanisms of T3 receptor (TR) action during vertebrate development. However, the lack of genomic sequence information, its tetraploid genome, and lengthy developmental cycle hinder further analyses on TR functions. In this regard, the highly related species, Xenopus tropicalis, is much more advantageous. Toward developing X. tropicalis for genome-wide and genetic studies of TR function, we analyzed the expression profiles of TRs and their heterodimerization partners, retinoid X receptors (RXRs) or 9-cis retinoic acid receptors. We show that their expression correlates with transformations in different organs and that TR/RXR heterodimers are capable of repressing and activating gene expression in vivo in the absence and presence of T3, respectively. We further demonstrate that TRs are bound to endogenous target genes in X. tropicalis tadpoles. Our results thus support a role of TRs in mediating the metamorphic effects of T3 in X. tropicalis. More importantly, the similarities in the expression and function between X. tropicalis and X. laevis TRs and RXRs as demonstrated by our study also pave the way to take advantages of existing morphological, molecular, and cellular knowledge of X. laevis development and the genetic and sequence superiority of X. tropicalis to dissect the molecular pathways governing tissue/organ-specific transformations during vertebrate postembryonic development.

SUBMITTER: Wang X

PROVIDER: S-EPMC2584584 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis.

Wang Xuedong X Matsuda Hiroki H Shi Yun-Bo YB

Endocrinology 20080717 11

Amphibian metamorphosis serves as an excellent model to study T3 function during postembryonic development in vertebrate due to its total dependence on T3. Earlier molecular studies in the model species Xenopus laevis have led to a number of important in vivo findings on the function and mechanisms of T3 receptor (TR) action during vertebrate development. However, the lack of genomic sequence information, its tetraploid genome, and lengthy developmental cycle hinder further analyses on TR functi ...[more]

PMID: 18635662

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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

Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis.

Publications

Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis.

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