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Profiling limb muscle degeneration by inducible dominant negative thyroid hormone receptor transgene over-expression

ABSTRACT: Premetamorphic Xenopus laevis tadpoles limbs develop in response to thyroid hormone by proliferation and subsequent differentiation. We have previously reported that inhibiting the thyroid hormone action using a dominant negative receptor in limbs of developing tadpoles inhibits its growth and the tadpole limb has almost no muscle. The goal of this experiment is to study the role of thyroid hormone in the maintenance of limb muscle using transgenic tadpoles carrying a doxycyline inducible dominant negative thyroid receptor transgene expressed exclusively in the muscle using a muscle specific promoter and identify the genes involved in the degenerative process . F1 progeny of transgenic Xenopus frogs and their nontransgenic siblings (at stages NF55 and NF66) were treated with 50µg doxycycline hyclate in 0.1 X MMR solution for 2 weeks or 6 weeks to induce the over-expression of the transgene. Limbs from the tadpoles were dissected at the end of the experiment. Keywords: development or differentiation design,reference design,replicate design,time series design

ORGANISM(S): Xenopus laevis

PROVIDER: GSE5249 | GEO | 2006/07/08

SECONDARY ACCESSION(S): PRJNA96467

REPOSITORIES: GEO

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Project description:Hydroxylated polychlorinated biphenyls are the metabolites produced from polychlorinated biphenyls (PCBs) by drug-metabolizing enzyme cytochrome P450 1A1. These compounds are bound to transthyretin, a major plasma thyroid hormone-binding protein in amphibian tadpoles. The compounds-transthyretin complexes are transferred into the brain across the blood brain barrier in mammals. Thus these compounds are suspected to disrupt neural development in brain. We studied about the effects of hydroxylated PCBs on the thyroid system in brain using metamorphosing tadpoles of African clawed toad, Xenopus laevis. The metamorphosis assay revealed that these compounds had inhibitory effects on the thyroid hormone-induced metamorphosis. This in vivo assay was a powerful tool to detect thyroid-disrupting activities, because we were not able to detect the inhibitory effects of these compounds using thyroid hormone-responsive reporter gene assay in a cultured Xenopus cell line. A genome-wide gene expression analysis in brain following short-term exposure to these compounds demonstrated that the delay of metamorphosis and the morphological thyroid-disrupting changes could be caused partially by disruption of the thyroid hormone-induced gene expression by hydroxylated PCBs. Furthermore, we associated functional ontology terms with the transcripts whose expression were altered by thyroid hormone alone, or thyroid hormone and hydroxylated PCBs. We suggested that these approachs using a technique of bioinformatics revealed molecular mechanism of thyroid-disrupting activities in vivo. Thyroid hormones induce amphibian metamorphosis and alter a lot of thyroid hormone-responsive gene expression. We studied about the effects of hydroxylated PCBs on TH-induced gene expression. Premetamorphic tadpoles were treated with 500 nM hydroxylated PCBs in the presence of 1 nM thyroid hormone for 4 days. After exposure period total RNA was extracted from brain. Study included at least three replicate of each treatment.

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Profiling limb muscle degeneration by inducible dominant negative thyroid hormone receptor transgene over-expression

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