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Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis.

Banker, D E and Eisenman, R N (1993) Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis. Molecular and cellular biology, 13 (12). pp. 7540-7552. ISSN 0270-7306

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Thyroid hormone receptor acts as a hormone-dependent transcriptional transactivator and as a transcriptional repressor in the absence of thyroid hormone. Specifically, thyroid hormone receptor can repress retinoic acid-induced gene expression through interactions with retinoic acid receptor. (Retinoic acid is a potent teratogen in the frog Xenopus laevis, acting at early embryonic stages to interfere with the formation of anterior structures. Endogenous retinoic acid is thought to act in normal anterior-posterior axis formation.) We have previously shown that thyroid hormone receptor RNA (alpha isotype) is expressed and polysome-associated during Xenopus embryogenesis preceding thyroid gland maturation and endogenous thyroid hormone production (D. E. Banker, J. Bigler, and R. N. Eisenman, Mol. Cell. Biol. 11:5079-5089, 1991). To determine whether thyroid hormone receptor might influence the effects of retinoic acid in early frog development, we have examined the results of ectopic thyroid hormone receptor expression on retinoic acid teratogenesis. We demonstrate that microinjections of full-length thyroid hormone receptor RNA protect injected embryos from retinoic acid teratogenesis. DNA binding is apparently essential to this protective function, as truncated thyroid hormone receptors, lacking DNA-binding domains but including hormone-binding and dimerization domains, do not protect from retinoic acid. We have shown that microinjections of these dominant-interfering thyroid hormone receptors, as well as anti-thyroid hormone receptor antibodies, increase retinoic acid teratogenesis in injected embryos, presumably by inactivating endogenous thyroid hormone receptor. This finding suggests that endogenous thyroid hormone receptors may act to limit retinoic acid sensitivity. On the other hand, after thyroid hormone treatment, ectopic thyroid hormone receptor mediates teratogenesis that is indistinguishable from the dorsoanterior deficiencies produced in retinoic acid teratogenesis. The previously characterized retinoic acid-responsive gene, Xhox.lab2, can be induced by thyroid hormone in embryos ectopically expressing thyroid hormone receptor and is less responsive to retinoic acid in such embryos. The fact that both thyroid hormone and retinoic acid can affect overlapping gene expression pathways to produce abnormal embryonic axes and can regulate the same early-expressed gene suggests a model in which thyroid hormone receptor blocks retinoic acid receptor-mediated teratogenesis by directly repressing retinoic acid-responsive genes.

Item Type: Article or Abstract
Additional Information: This article is freely available in PubMed Central and at the journal's website.
PubMed ID: 7504177
PMCID: PMC364826
Grant Numbers: MG-66242
Keywords or MeSH Headings: Animals; Base Sequence; Biological Markers; DNA, Complementary/genetics; Embryonic and Fetal Development/genetics/physiology; Gene Expression/drug effects; Molecular Sequence Data; RNA/genetics; Receptors, Retinoic Acid/genetics/physiology; Receptors, Thyroid Hormone/genetics/physiology; Teratogens/pharmacology; Tretinoin/pharmacology; Triiodothyronine/pharmacology; Xenopus laevis;
Subjects: Cellular and Organismal Processes > Development
Molecules > Proteins > Receptors
Cellular and Organismal Processes > Genetic processes > Transcription
Depositing User: Library Staff
Date Deposited: 01 Dec 2008 21:37
Last Modified: 21 May 2010 23:03

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