Molecular and genetic studies suggest that thyroid hormone receptor is both necessary and sufficient to mediate the developmental effects of thyroid hormone

Abstract

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.

Identification of differentially expressed thyroid hormone responsive genes from the brain of the Mexican Axolotl (Ambystoma mexicanum)

“…In A. t. tigrinum , thyroid hormone increases during larval development (Norman et al, 1987) and this is thought to initiate metamorphosis through thyroid hormone receptors, as has been shown in anurans (Das et al, 2010). Hundreds of transcripts were observed to show the same temporal patterns of change between A. t. tigrinum and A. mexicanum , including genes associated with neural development and maturation.…”

“…Anuran amphibians in particular have been extensively studied because it is straightforward to induce metamorphosis in tadpoles with TH and investigate how TH affects developmental changes in vivo through interactions with TRs, accessory co-factors, and changes in chromatin state (e.g. Shi, 2000; Das et al, 2010; Bilesimo et al, 2011). TH levels increase precipitously during anuran metamorphosis to regulate the development of adult tissue and organ systems from pre-existing larval structures and progenitor cell populations.…”

Growth, Development, and Intestinal Remodeling Occurs in the Absence of Thyroid Hormone Receptor α in Tadpoles of Xenopus tropicalis

“…An additional complication is that fetal tissues are constantly exposed to maternal TH through the placenta (4), such that manipulation of fetal TH signaling is difficult to achieve without potentially introducing artefacts from altered maternal TH physiology. Frog metamorphosis has served as an excellent model to study the developmental roles of TRs (2, [13][14][15][16][17]. The dramatic TH-dependent molecular and morphological changes that occur during metamorphosis are unrivaled among terrestrial vertebrates, where signaling via TH and their receptors is necessary and sufficient to initiate nearly all developmental events during metamorphosis.…”

Higher thyroid hormone receptor expression correlates with short larval periods in spadefoot toads and increases metamorphic rate

“…As TRs are central to TH signaling and metamorphosis [9], altered TR expression among species was a prime candidate for an evolutionary change that could explain the faster tail shrinkage and by extension the shorter larval period duration in S. couchii . Frogs, like all vertebrates, have two TR genes, TRα and TRβ [48].…”