Asymmetric growth and development of the Xenopus laevis retina during metamorphosis is controlled by type III deiodinase

During the metamorphosis of the Xenopus laevis retina, thyroid hormone (TH) preferentially induces ventral ciliary marginal zone (CMZ) cells to both increase their proliferation and give rise to ipsilaterally projecting ganglion cells. Here we show that dorsal CMZ cells express type III deiodinase (D3), an enzyme that inactivates TH. The dorsal CMZ cells can be induced to proliferate if deiodinase activity is inhibited. D3 or dominant-negative thyroid hormone receptor transgenes inhibit both TH-induced proliferation of the ventral CMZ cells and the formation of the ipsilateral projection. Thus, the localized expression of D3 in the dorsal CMZ cells accounts for the asymmetric growth of the frog retina.     

The presence of an embryonic opercular flap in amniotes

The operculum is a large flap consisting of several flat bones found on the side of the head of bony fish. During development, the opercular bones form within the second pharyngeal arch, which expands posteriorly and comes to cover the gill-bearing arches. With the evolution of the tetrapods and the assumption of a terrestrial lifestyle, it was believed that the operculum was lost. Here, we demonstrate that an embryonic operculum persists in amniotes and that its early development is homologous with that of teleosts. As in zebrafish, the second pharyngeal arch of the chick embryo grows disproportionately and comes to cover the posterior arches. We show that the developing second pharyngeal arch in both chick and zebrafish embryos express orthologous genes and require shh signalling for caudal expansion. In amniotes, however, the caudal edge of the expanded second arch fuses to the surface of the neck. We have detailed how this process occurs and also demonstrated a requirement for thyroid signalling here. Our results thus demonstrate the persistence of an embryonic opercular flap in amniotes, that its fusion mirrors aspects of amphibian metamorphosis and gives insights into the origin of branchial cleft anomalies in humans.     

Amphibian metamorphosis as a model for studying the developmental actions of thyroid hormone

The thyroid hormones L-thyroxine and triiodo-Lthyronine have profound effects on postenbryonic development of most vertebrates.Analysis of their action in mammals is vitiated by the exposure of the developing foetus to a number of maternal factors which do not allow one to specifically define the role of thyroid hormone (TH) or that of other hormones and factors that modulate its action.Amphibian metamorphosis is obligatorily dependent on TH which can initiate all the diverse physiological manifestations of this postembryonic developmental process(morphogenesis,cell death,re-structuring,etc.) in free-living embryos and larvas of most anurans.This article will first describe the salient features of metamorphosis and its control by TH and other hormones.Emphasis will be laid on the key role played by TH receptor (TR),in particular the phenomenon of TR gene autoinduction,in initiating the developmental action of TH.Finally,it will be argued that the findings on the control of amphibian metamorphosis enhance our understanding of the regulation of postembryonic development by TH in other vertebrate species.     

Transforming growth factor-beta5 expression during early development of Xenopus laevis

Members of the transforming growth factor-beta (TGF-beta) superfamily play various roles during development in both vertebrates and invertebrates. Two isoforms, TGF-beta2 and -beta5, have been isolated from Xenopus laevis. We describe here the localization of TGF-beta5 mRNA in early embryos of X. laevis, assessed by whole-mount in situ hybridization. The first detectable expression of TGF-beta5 was seen in the stage 14 embryo at the posterior tip of notochord, which continued to later stages, accompanied by the expression in bilateral regions of posterior wall in the tail region next to the notochord. At later stages, transient expression was seen in the cement gland (around stage 21) and in the somites (stages 24-27). In addition, expression was present in the branchial arches (stage 29-36) and olfactory placodes (stage 36).     

甲状腺激素在两栖动物变态过程中的作用

两栖动物的幼体变态是研究甲状腺激素调节组织和器官重构的理想模式。本文主要综述了近年来两栖动物甲状腺激素合成过程中3种脱碘酶D1、D2和D3的特点及其生物学功能;甲状腺激素受体的蛋白结构、类型和机能;以及甲状腺激素对两栖动物幼体变态过程中各个类型组织和器官重构的调节;甲状腺激素、甲状腺激素受体和脱碘酶的互作,并展望了今后的研究方向。     

One of the duplicated matrix metalloproteinase-9 genes is expressed in regressing tail during anuran metamorphosis

The drastic morphological changes of the tadpole are induced during the climax of anuran metamorphosis, when the concentration of endogenous thyroid hormone is maximal. The tadpole tail, which is twice as long as the body, shortens rapidly and disappears completely in several days. We isolated a cDNA clone, designated as Xl MMP-9TH, similar to the previously reported Xenopus laevis MMP-9 gene, and showed that their Xenopus tropicalis counterparts are located tandemly about 9 kb apart from each other in the genome. The Xenopus MMP-9TH gene was expressed in the regressing tail and gills and the remodeling intestine and central nervous system, and induced in thyroid hormone-treated tail-derived myoblastic cultured cells, while MMP-9 mRNA was detected in embryos. Three thyroid hormone response elements in the distal promoter and the first intron were involved in the upregulation of the Xl MMP-9TH gene by thyroid hormone in transient expression assays, and their relative positions are conserved between X. laevis and X. tropicalis promoters. These data strongly suggest that the MMP-9 gene was duplicated, and differentiated into two genes, one of which was specialized in a common ancestor of X. laevis and X. tropicalis to be expressed in degenerating and remodeling organs as a response to thyroid hormone during metamorphosis.     

Expression of type II iodothyronine deiodinase marks the time that a tissue responds to thyroid hormone-induced metamorphosis in Xenopus laevis

The thyroid gland synthesizes thyroxine (T4), which passes through the larval tadpole's circulatory system. The enzyme type II iodothyronine deiodinase (D2) converts thyroxine (T4) to the active hormone 3,5,3'-triiodothyronine (T3) in peripheral tissues. An early response to thyroid hormone (TH) in the Xenopus laevis tadpole is the stimulation of cell division in cells that line the brain ventricles, the lumen of the spinal cord, and the limb buds. These cells express constitutively high levels of D2 mRNA. Exogenous T4 induces early DNA synthesis in brain, spinal cord, and limb buds as efficiently as T3. The deiodinase inhibitor iopanoic acid blocks T4- but not T3-induced cell division. At metamorphic climax, both TH-induced cell division and D2 expression decrease in the brain. Then D2 expression appears in late-responding tissues including the anterior pituitary, the intestine, and the tail where cell division is reduced or absent. Therefore, constitutive expression of D2 occurs in the earliest target tissues of TH that will grow and differentiate, while TH-induced expression of D2 takes place in late-responding tissues that will remodel or die. This pattern of constitutive and induced D2 expression contributes to the timing of metamorphic changes in these tissues.     

Metabolism of the thyroid hormones

This review covers the current knowledge about the various metabolic pathways involved in the conversion of thyroid hormones to the thyromimetically active and inactive iodothyronines. The concerted mechanism of systemic and local production of iodothyronines by tissue-specific iodothyronine deiodinase isozymes will ultimately determine the expression of thyroid hormone action. This is exemplified for the regulation of synthesis and release of TSH by iodothyronines at the pituitary level. Iodothyronine metabolites, e.g. Triac, rT3 and T3 amine may modulate TSH secretion, and alterations of local pituitary deiodination (e.g. iopanoate inhibition) influence diurnal TSH secretion without changing TRH-dependent episodic TSH secretion pattern. A summary of structure-activity relationships of greater than 200 naturally occurring and synthetic ligands of rat liver type I iodothyronine deiodinase isozyme propylthiouracil-sensitive) in vitro allows the design of iodothyronine analogues which either serve as specific substrates or antagonists of iodothyronine binding and metabolizing proteins. Furthermore, a complete picture of the ligand-complementary active site of the type I isozyme can be derived. A synthetic 'structurally optimized' iodothyronine-analogue flavonoid inhibitor of the type I deiodinase is able to displace T4 from binding to thyroxine-binding prealbumin and leads to unexpected organ-specific alterations of thyroid hormone metabolism and expression of thyroid hormone actions in an animal model. Therefore, for a complete understanding of thyroid hormone metabolism and action, thyroid hormone transport, cellular compartmentalization, and alternate pathways also have to be considered.     

Role of type III iodothyronine 5-deiodinase gene expression in temporal regulation of Xenopus metamorphosis

To elucidate the role of type III iodothyronine 5-deiodinase (5-D) in the temporal regulation of amphibian metamorphosis, the regulation of gene expression of 5-D and thyroid hormone receptor beta (TRbeta) in organs of Xenopus laevis was investigated. High levels of TRbeta mRNA in the respective organs were observed at the times of their major morphological changes. Expression of the 5-D gene was highly regulated among the organs during metamorphosis, including up-regulation in the tail and down-regulation in the liver. The tail and liver expressed 5-D gene before their metamorphic changes. These precocious expressions correlated with the lower responsiveness to exogenously added triiodo-L-thyronine (T3) for inducing a high level of TRbeta mRNA expression. However, the same organs responded to lower doses of T3 to regulate 5-D gene expression as seen in spontaneous metamorphosis. The induction of 5-D gene expression was considerably delayed in the intestine, even at an excess dose of T3. Thus, the two genes in a given organ appeared to respond to T3 either with different dose dependencies or with different timetables. The results obtained are also discussed in respect to recent findings in Rana catesbeiana.     

Histo-morphology of the thyroid gland during the larval development of Pleurodema borellii (Anura,Leptodactylidae)

The thyroid gland is essential in anurans, since thyroid hormones (TH) are the main regulators of larval development. Its absence or inactivity interrupts development and precludes metamorphosis. Histological changes are important diagnostic criteria for evaluating thyroid gland activity. However, there is a large larval diversity where the development of the thyroid gland development has not been studied. Pleurodema borellii is an anuran from northwest of Argentina with typical omnivorous pond tadpoles that can be easily raised in captivity. This study explores the histo-morphological changes of the thyroid gland architecture during larval development. Histological parameters indicate peak glandular activity in parallel with the intensity of the metamorphic transformations. These parameters regress towards the end of metamorphosis, indicating low TH release. P. borellii's thyroid gland does not appear to have relevant activity in post-metamorphic juvenile stages. This study is a first step towards understanding endocrine regulation during the development of Pleurodema borellii, and a reference to future studies in this species involving thyroid-dependent processes.     

Amphibian metamorphosis as a model for studying the developmental actions of thyroid hormone.

The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on postembryonic development of most vertebrates. Analysis of their action in mammals is vitiated by the exposure of the developing foetus to a number of maternal factors which do not allow one to specifically define the role of thyroid hormone (TH) or that of other hormones and factors that modulate its action. Amphibian metamorphosis is obligatorily dependent on TH which can initiate all the diverse physiological manifestations of this postembryonic developmental process (morphogenesis, cell death, re-structuring, etc.) in free-living embryos and larvae of most anurans. This article will first describe the salient features of metamorphosis and its control by TH and other hormones. Emphasis will be laid on the key role played by TH receptor (TR), in particular the phenomenon of TR gene autoinduction, in initiating the developmental action of TH. Finally, it will be argued that the findings on the control of amphibian metamorphosis enhance our understanding of the regulation of postembryonic development by TH in other vertebrate species.     

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T₄) to the more metabolically active 3,3′-5 triiodothyronine (T₃). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [¹²⁵I]N-bromoacetyl reverse triiodothyronine, is also labeled with⁷⁵Se by in vivo treatment of rats with⁷⁵Se-Na₂SeO₃. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.     

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T₄) to the more metabolically active 3,3′–5 triiodothyronine (T₃). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [¹²⁵I]N-bromoacetyl reverse triiodothyronine, is also labeled with⁷⁵Se by in vivo treatment of rats with⁷⁵Se−Na₂SeO₃. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.