Induction of Larval Tissue Resorption in Xenopus laevis Tadpoles by the Thyroid Hormone Receptor Agonist GC-1 (original) (raw)
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Genes to Cells, 2012
During amphibian metamorphosis, a series of dynamic changes occur in a predetermined order. Hind limb morphogenesis begins in response to low levels of thyroid hormone (TH) in early prometamorphosis, but tail muscle cell death is delayed until climax, when TH levels are high. It takes about 20 days for tadpoles to grow from early prometamorphosis to climax. To study the molecular basis of the timing of tissue-specific transformations, we introduced thyroid hormone receptor (TR) expression constructs into tail muscle cells of Xenopus tadpoles. The TR-transfected tail muscle cells died upon exposure to a low level of thyroxine (T4). This cell death was suggested to be mediated by type 2 iodothyronine deiodinase (D2) that converts T4 to T3-the more active form of TH. D2 mRNA was induced in the TR-overexpressing cells by low levels of TH. D2 promoter contains a TH-response element (TRE) with a lower affinity for TR. These results show that the TR transfection confers the ability to respond to physiological concentrations of TH at early prometamorphosis to tail muscle cells through D2 activity and promotes TH signaling. We propose the positive feedback loop model to amplify the cell's ability to respond to low levels of T4.
Molecular and Cellular Biology, 2002
Thyroid hormone receptors (TR) act as activators of transcription in the presence of the thyroid hormone (T 3 ) and as repressors in its absence. While many in vitro approaches have been used to study the molecular mechanisms of TR action, their physiological relevance has not been addressed. Here we investigate how TR regulates gene expression during vertebrate postembryonic development by using T 3 -dependent amphibian metamorphosis as a model. Earlier studies suggest that TR acts as a repressor during premetamorphosis when T 3 is absent. We hypothesize that corepressor complexes containing the nuclear receptor corepressor (N-CoR) are key factors in this TR-dependent gene repression, which is important for premetamorphic tadpole growth.
Journal of Biological Chemistry
Greater than 90% of the endogenous thyroid hormone receptor proteins TRa and TRP in tissues of Xenopus Zaevis comigrate with their respective in uitro synthesized counterparts, and these major components are not phosphorylated detectably. Maternally inherited TRa protein is stable through early embryogenesis during a time in which there is no detectable TRa mRNA synthesis. At stage 35 when TRa mRNA is first detectable, the inherited T R a protein is present at about 100 molecules/ cell. TRa protein subsequently increases to levels of about 1500 and 6000 moleculedcell in tail and head regions, respectively, in stage 52 tadpoles. Even though TRa mRNA gradually increases during metamorphosis (from stage 52 to 62), TRa protein remains constant, suggesting strongly that post-transcriptional events control the ultimate levels of TRa protein. In contrast, there is no detectable TRP protein (less than 100 moleculedcell) throughout embryogenesis until stage 52. Both TRP mRNA and protein rise along with the increase in endogenous thyroid hormone, reaching a maximum at the climax of metamorphosis, when TRP protein exceeds TRa protein in concentration. As with TRa protein, TR/3 protein in tail is consistently about one-fourth that of T R p protein in the head region. The number of T R a protein molecules in extracts of premetamorphic tadpoles and cultured cells grown in the absence of thyroid hormone fully accounts for all of the sites to which "'I-T, bind. W e interpret this to mean that TRa protein must be a necessary, if not sufficient, component in the pathway toward metamorphosis triggered by thyroid hormone and required for the phenomenon of competence in tissues and cells.
Journal of Applied Toxicology, 2012
ABSTRACTThyroid hormones are essential for the regulation of a wide range of biological processes associated with normal development and metabolism in vertebrates. For the screening of chemicals with a potential thyroid hormone and anti‐thyroid hormone activities, we have established transient transactivation assay systems using thyroid hormone receptors (TRα and TRβ) from three frog species (Xenopus laevis, Silurana tropicalis and Rana rugosa), a fish (Oryzias latipes), an alligator (Alligator mississippiensis) and a human (Homo sapiens). In all species examined, similar transcriptional activities were found for triiodothyronine (T3: 10–11 M in TRα and 10–10 M in TRβ) and thyroxine (T4: 10–9 M in TRα and 10–8 M in TRβ). Analogs of thyroid hormone (3,5,3′,‐triiodothyroacetic acid and 3,3′,5,5′‐tetraiodothyroacetic acid) exhibited weaker activity, requiring 10‐fold higher concentrations for induction of activity when compared with T3 and T4. These results provide support for the usef...
Xenopus laevis as a model for studying thyroid hormone signalling: From development to metamorphosis
Molecular and Cellular Endocrinology, 2008
Please cite this article as: Morvan-Dubois, G., Demeneix, B.A., Sachs, L.M., Xenopus laevis as a model for studying thyroid hormone signalling: From development to metamorphosis, Molecular and Cellular Endocrinology (2007), A c c e p t e d M a n u s c r i p t 1 Xenopus laevis as a model for studying thyroid hormone signalling: from development to metamorphosis. Summary 150 words Introduction: Xenopus leavis and thyroid hormone signalling.
Dual functions of thyroid hormone receptors during Xenopus development
Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 2000
Thyroid hormone (TH) plays a causative role in anuran metamorphosis. This effect is presumed to be manifested through the regulation of gene expression by TH receptors (TRs). TRs can act as both activators and repressors of a TH-inducible gene depending upon the presence and absence of TH, respectively. We have been investigating the roles of TRs during Xenopus lae6is development, including premetamorphic and metamorphosing stages. In this review, we summarize some of the studies on the TRs by others and us. These studies reveal that TRs have dual functions in frog development as reflected in the following two aspects. First, TRs function initially as repressors of TH-inducible genes in premetamorphic tadpoles to prevent precocious metamorphosis, thus ensuring a proper period of tadpole growth, and later as activators of these genes to activate the metamorphic process. Second, TRs can promote both cell proliferation and apoptosis during metamorphosis, depending upon the cell type in which they are expressed.
Biochemistry, 1985
To explore the role of thyroid hormones in organ remodeling during the metamorphosis of amphibians, the cDNAs of two thyroid hormone receptors (TRα and TRβ) in Rana chensinensis were identified. The 1257 bp of rcTRα cDNA encoding 418 amino acids and the 1122 bp of rcTRβ cDNA encoding 373 amino acids were cloned. Their polypeptide sequences contain two highly conserved cysteine-rich zinc fingers in the DNA-binding domain, while rcTRβ is 42 amino acids shorter in its A/B domain when compared with rcTRα. Fifty-five amino acids differed between the TRα and TRβ domains. The rcTRα and rcTRβ mRNA levels in the liver, brain, skin, and tail of tadpoles were analyzed via qRT-PCR during metamorphosis. The results showed that the changes of rcTRα mRNA levels were moderate while those of rcTRβ were dramatic in all 4 tissues during metamorphosis. In addition, the levels of rcTRβ mRNA were relatively low at premetamorphosis and reached a peak around the climax. Tissue-specific expression of rcTRα and rcTRβ suggests that thyroid hormones play various roles in different organs or tissues at different developmental stages of metamorphosis.
General and Comparative Endocrinology, 2010
Thyroid hormone (TH) affects diverse biological processes and can exert its effects through both gene regulation via binding the nuclear TH receptors (TRs) and non-genomic actions via binding to cell surface and cytoplasmic proteins. The critical importance of TH in vertebrate development has long been established, ranging from the formation of human cretins to the blockage of frog metamorphosis due the TH deficiency. How TH affects vertebrate development has been difficult to study in mammals due to the complications associated with the uterus-enclosed mammalian embryos. Anuran metamorphosis offers a unique opportunity to address such an issue. Using Xenopus as a model, we and others have shown that the expression of TRs and their heterodimerization partners RXRs (9-cis retinoic acid receptors) correlates temporally with metamorphosis in different organs in two highly related species, Xenopus laevis and Xenopus tropicalis. In vivo molecular studies have shown that TR and RXR are bound to the TH response elements (TREs) located in TH-inducible genes in developing tadpoles of both species. More importantly, transgenic studies in Xenopus laevis have demonstrated that TR function is both necessary and sufficient for mediating the metamorphic effects of TH. Thus, the non-genomic effects of TH have little or no roles during metamorphosis and likely during vertebrate development in general.
Endocrinology
Thyroid hormone (TH) binds TH receptor α (TRα) and β (TRβ) to induce amphibian metamorphosis. Whereas TH signaling has been well studied, functional differences between TRα and TRβ during this process have not been characterized. To understand how each TR contributes to metamorphosis, we generated TRα- and TRβ-knockout tadpoles of Xenopus tropicalis and examined developmental abnormalities, histology of the tail and intestine, and messenger RNA expression of genes encoding extracellular matrix–degrading enzymes. In TRβ-knockout tadpoles, tail regression was delayed significantly and a healthy notochord was observed even 5 days after the initiation of tail shortening (stage 62), whereas in the tails of wild-type and TRα-knockout tadpoles, the notochord disappeared after ∼1 day. The messenger RNA expression levels of genes encoding extracellular matrix–degrading enzymes (MMP2, MMP9TH, MMP13, MMP14, and FAPα) were obviously reduced in the tail tip of TRβ-knockout tadpoles, with the sho...