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.     

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.     

Autoinduction of nuclear hormone receptors during metamorphosis and its significance

Metamorphosis is a most dramatic example of hormonally regulated genetic reprogramming during postembryonic development. The initiation and sustenance of the process are under the control of ecdysteroids in invertebrates and thyroid hormone, 3,3', 5-triiodothyronine, in oviparous vertebrates. Their actions are inhibited or potentiated by other endogenous or exogenous hormones - juvenile hormone in invertebrates and prolactin and glucocorticoids in vertebrates. The nuclear receptors for ecdysteroids and thyroid hormone are the most closely related members of the steroid/retinoid/thyroid hormone receptor supergene family. In many pre-metamorphic amphibia and insects, the onset of natural metamorphosis and the administration of the exogenous hormones to the early larvae are characterized by a substantial and rapid autoinduction of the respective nuclear receptors. This review will largely deal with the phenomenon of receptor autoinduction during amphibian metamorphosis, although many of its features resemble those in insect metamorphosis.In the frog Xenopus, thyroid hormone receptor autoinduction has been shown to be brought about by the direct interaction between the receptor protein and the thyroid-responsive elements in the promoter of its own gene. Three lines of evidence point towards the involvement of receptor autoinduction in the process of initiation of amphibian metamorphosis: (1) a close association between the extent of inhibition or potentiation by prolactin and glucocorticoid, respectively, and metamorphic response in whole tadpoles and in organ and cell cultures; (2) thyroid hormone fails to upregulate the expression of its own receptor in obligatorily neotenic amphibia but does so in facultatively neotenic amphibia; and (3) dominant-negative receptors known to block hormonal response prevent the autoinduction of wild-type Xenopus receptors in vivo and in cell lines.Autoinduction is not restricted to insect and amphibian metamorphic hormones but is also a characteristic of other nuclear receptors (e.g., retinoid, sex steroids, vitamin D(3) receptors) where the ligand is involved in a postembryonic developmental function. A wider significance of such receptor autoregulation is that the process may also be important for mammalian postembryonic development.     

Evolutionary significance of the phylogenetic distribution of the mammalian hypothalamic releasing hormones

The hypophysiotrophic hormones isolated from the mammalian hypothalamus are distributed throughout the nervous system of vertebrate species. Although their role in regulating pituitary hormone secretion in mammals is clear, a similar function in lower species has not been established. Thyrotropin-releasing hormone is unable to stimulate thyroid function in amphibia and fish, despite being present in the hypothalamus and brain of these species of high concentration. The tripeptide is also found in high concentration in frog skin, a tissue derived from (or programed by) primitive neuroectoderm that is also a rich source of other peptides structurally related to neural peptides located in mammalian brain and gut. Luteinizing hormone-releasing hormone (LHRH) is able to activate gonadotropin secretion in submammalian species but there is evidence that the LHRH material present in avian, reptilian, and piscine brain is not identical to the mammalian decapeptide. An LHRH-like material present in frog sympathetic ganglia appears to function as a neurotransmitter in this location. Somatostatin is present in high concentrations in the hypothalamus, brain, pancreas, and gastrointestinal tract of all vertebrates and chromatographically is identical to the mammalian material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It an material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It an material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It appears likely that the releasing hormones initially arose with a neurocrine or paracrine function, and that only later in evolution did they acquire the role of regulating adenohypophysial secretion.     

Is Lamprey Metamorphosis Regulated by Thyroid Hormones?

Lampreys are one of just a few fishes which have a true (firstor first type) of metamorphosis in their life cycle. In thesea lamprey (Petromyzon marinus), spontaneous metamorphosisis initiated when the size (length and weight), condition factor,and lipid stores reach appropriate levels and coincide withthe postwinter rise in water temperature. The serum levels ofthe thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃),drop dramatically at the onset of metamorphosis and metamorphosiscan be induced with treatment of animals with the goitrogen,KCIO₄, which also results in a decline in serum levels of thyroidhormones. The fact that thyroid hormone treatment can blockspontaneous and induced metamorphosis is support for the viewthat thyroid hormones, particularly T₃, operates like a juvenilehormone in lamprey metamorphosis; this view is counter to therole of thyroid hormones in metamorphosis of other vertebrates.The monodeiodinase pathways, whereby T₄ is converted to T₃ orto the biologically inactive reverse T₃, and even further degradationof T₃, may be a significant mechanism directing metamorphicchange. Lamprey metamorphosis is facultative in that it is initiatedor inhibited depending upon the coordination of a complex integrationof environmental, metabolic and hormonal cues. Thyroid hormonesdo not regulate lamprey metamorphosis in the sense observedin other vertebrate metamorphoses but they are important tothe developmental process. Some of the features of the involvementof thyroid hormones in lamprey metamorphosis may be relatedto the presence of the endostyle in larvae which in turn reflectsthe ancient origins of this vertebrate and perhaps the conservationof an ancient method of induction of metamorphosis. Some cluefor other factors which initiate lamprey metamorphosis may comethrough the examination of inducers of metamorphosis in lowerchordates     

Hormones of youth?

Ageing is doubtless complicated, lifelong process regarding many body systems, including endocrine system. Human hormonal system changes with age. Although these changes concern secretion of many hormones, they are not unidirectional, there are hormones secretion of which is diminished, whereas secretion of the others is augmented or not changed with age. A possible role of hormones which are often termed "hormones of youth"(growth hormone, melatonin, and dehydroepiandrosterone) in the ageing process is discussed in the present article. Although some experimental and clinical data indicate that these hormones may play some role in the human ageing process, it appears from presented data that we are still far away from conclusion that, indeed, one (or more) of the discussed hormones could be considered as "hormone of youth", which may slow down ageing process. However, some symptoms of the quality of life improvement following administration of dehydroepiandrosterone, melatonin, and growth hormone may suggest that they may promote so called "successful aging".     

Tadpole competence and tissue-specific temporal regulation of amphibian metamorphosis: Roles of thyroid hormone and its receptors

Amphibian metamorphosis is a post-embryonic process that systematically transforms different tissues in a tadpole. Thyroid hormone plays a causative role in this complex process by inducing a cascade of gene regulation. While natural metamorphosis does not occur until endogenous thyroid hormone has been synthesized, tadpoles are competent to respond to exogenous thyroid hormone shortly after hatching. In addition, even though the metamorphic transitions of individual organs are all controlled by thyroid hormone, each occurs at distinct developmental stages. Recent molecular studies suggest that this competence of premetamorphic tadpoles to respond to the hormone and the developmental stage-dependent regulation of tissue-specific transformations are determined in part by the levels of thyroid hormone receptors and the concentrations of cellular free thyroid hormone. In addition, at least two genes, encoding a cytosolic thyroid hormone binding protein and a 5-deiodinase, respectively, are likely to be critical players in regulating cellular free thyroid hormone concentrations. This review discusses how all of these molecuar components coordinate to induce amphibian metamorphosis in a correct spatial and temporal manner. These studies provde us with general clues as to how and why tissues become competent to respond to hormonal signals.     

Endocrine Effects on Migration

Migratory behavior and flight metabolism are influenced by manyneuroendocrine factors. In fish engaged in migration from freshwater to the sea, prolactin and/or thyroid hormones often playkey roles in migration and salinity preference. Prolactin inducesmigration to the water and the changes of second metamorphosisin a number of amphibians, and thyroid hormone may stimulatemovement away from water. In birds there is evidence that prolactin,cortical steroids, thyroid hormones, gonadotropins and gonadalsteroids can all influence migration; considerable interspeciesvariation exists. Juvenile hormone stimulates oogenesis and migratory behaviorin several insects, but has no effect or causes flight muscledegeneration in others. It may serve to coordinate oogenesis,adult diapause and migration, particularly in colonizing species.Other neuroendocrine products have been implicated in controlof migratory behavior or flight metabolism of insects includingecdysone, adipokinetic hormones and octopamine.     

Induction of metamorphosis in the sand dollar Peronella japonica by thyroid hormones

The larva of the sand dollar Peronella japonica lacks a mouth and gut, and undergoes metamorphosis into a juvenile sand dollar without feeding. In the present study, it was found that thyroid hormones accelerate the metamorphosis of P. japonica larvae. The contents of thyroid hormones in larvae increased gradually during development. Thiourea and potassium perchlorate, inhibitors of thyroid hormone synthesis, delayed larval metamorphosis and simultaneously repressed an increase in the content of thyroxine in the larval body. These results suggest that the P. japonica larva has a system for synthesis of thyroid hormones that act as factors for inducing metamorphosis.     

Gene expression during metamorphosis: An ideal model for post-embryonic development

The precocious induction in vivo and in culture of insect and amphibian metamorphosis by exogenous ecdysteroids and thyroid hormones, and its retardation or inhibition by juvenile hormone and prolactin, respectively, has allowed the analysis of such diverse processes of post-embryonic development as morphogenesis, tissue remodelling, functional reorganization, and programmed cell death. Metamorphosis in vertebrates also shares many similarities with mammalian development in the late foetal and perinatal period. This review describes the regulation of expression of some of the ‘adult’ gene products during metamorphosis in invertebrates and vertebrates. Recent studies on metamorphosis have revealed the important role played by auto-induction of hormone receptor genes, based on which a model will be presented to explain the activation of ‘downstream’ genes which give rise to the adult phenotype. It will also be argued that metamorphosis is an ideal model for analyzing some of the major mechanisms governing post-embryonic development.     

Comparative analysis of thyroxine distribution in ascidian larvae

The ascidian endostyle is a mucus-secreting pharyngeal organ, it has iodine-concentrating activity and the biosynthesis of thyroid hormones has been well documented. According to our recent findings, ascidians possess thyroid hormones, which are localized in mesenchymal cells. We have studied the presence and localization of l-thyroxine (T₄) in Ascidia malaca (Traustedt), Ascidiella aspersa (Müller), Phallusia mamillata (Cuvier) and Ciona intestinalis (Linnaeus) larvae and its involvement in metamorphosis. In vivo treatment of swimming larvae with exogenous T₄ and thiourea (a thyroid hormone synthesis inhibitor), demonstrate the presence of T4 during larval development. These results were confirmed by in vitro experiments utilizing dot blotting, radioimmunoassay and immunoperoxidase staining. The hormone was localized in mesenchymal cells of all four ascidians, spread out in the body cavity, under the adhesive papillae and around the intestine. The presence of TH in mesenchymal cells could be related to blood cells, musculature and heart tissue differentiation. The results suggest that this hormone could be involved in the control of metamorphosis.     

Role of thyroid hormones in the normal and glucocorticosteroid hormone-induced evolution of carbamoyl-phosphate synthase (ammonia) activity in axolotl liver.

1. In axolotl liver, the activity of carbamoyl-phosphate synthase (ammonia), expressed per mg liver protein, decreases to a minimum at 5 months of age, then increases to a maximum at 8 months of age which is followed by a decrease again. The initial decrease between 3 and 5 months of age appears to be largely due to an increase in non-carbamoyl-phosphate synthase protein and the following increase between 5 and 8 months of age to a relative increase of carbamoyl-phosphate synthase protein. 2. Treatment of the animals with triiodothyronine causes an increase in carbamoyl-phosphate synthase activity, the extent of which is dependent upon hormone concentration and age of the animal. After 8 months of age no increase of enzyme occurs upon thyroid hormone treatment, although metamorphosis occurs. 3. Glucocorticosteroid hormones stimulate carbamoyl-phosphate synthase activity 2-to 3-fold in animals older than 6 months. However, in animals younger than 6 months, low concentrations of thyroid hormone, insufficient to induce metamorphosis, are necessary as permissive agents. 4. The stimulatory effects of high concentrations of thyroid hormones (T3) on carbamoyl-phosphate synthase appear to be mediated via a stimulatory effect on glucocorticosteroid biosynthesis. 5. The natural rise in enzyme activity between 5 and 8 months of age seems to be due to a rise in the concentration of circulating glucocorticosteroid hormones.     

Comparing thyroid and insect hormone signaling

Transitions between different states of development, physiology,and life history are typically mediated by hormones. In insects,metamorphosis and reproductive maturation are regulated by aninteraction between the sesquiterpenoid juvenile hormone (JH)and the steroid 20-hydroxy-ecdysone (20E). In vertebrates andsome marine invertebrates, the lipophilic thyroid hormones (THs)affect metamorphosis and other life history transitions. Interestingly,when applied to insects, THs can physiologically mimic manyfacets of JH action, suggesting that the molecular actions ofTHs and JH/20E might be similar. Here we discuss functionalparallels between TH and JH/20E signaling in insects, with aparticular focus on the fruit fly, Drosophila melanogaster,a genetically and physiologically tractable model system. Comparingthe effects of THs with the well defined physiological rolesof insect hormones such as JH and 20E in Drosophila might provideimportant insights into hormone function and the evolution ofendocrine signaling.     

Epidermal growth factor (EGF) inhibits stimulated thyroid hormone secretion in the mouse

It is known that epidermal growth factor (EGF) inhibits iodide uptake in the thyroid follicular cells and lowers plasma levels of thyroid hormones upon infusion into sheep and ewes. In this study, the effects of EGF on basal and stimulated thyroid hormone secretion were investigated in the mouse. Mice were pretreated with 125I and thyroxine; the subsequent release of 125I is an estimation of thyroid hormone secretion. It was found that basal radioiodine secretion was not altered by intravenous injection of EGF (5 micrograms/animal). However, the radioiodine secretion stimulated by both TSH (120 microU/animal) and vasoactive intestinal peptide (VIP; 5 micrograms/animal) were inhibited by EGF (5 micrograms/animal). At a lower dose level (0.5 microgram/animal), EGF had no influence on stimulated radioiodine secretion. In conclusion, EGF inhibits stimulated thyroid hormone secretion in the mouse.     

Regulation of Metamorphosis-Associated Changes in the Lipid Metabolism of Selected Vertebrates

SYNOPSIS. The life histories of many vertebrates include complex,postembryonic developmental pathways that involve morphologicaland physiological changes that adapt juveniles to a new habitat.A survey of such developmental pathways, including lamprey metamorphosis,salmonid smoltification, and anuran metamorphosis, reveals acommon strategy of lipid metabolism consisting of two distinctphases. The first phase is characterized by lipid accumulationin storage sites and resultsfrom lipogenesis prevailing overlipolysis. The second phase is characterized by lipid depletionfrom storage sites and results from lipolysis prevailing overlipogenesis. Regulation of lipid deposition and lipid mobilizationis essential for ensuring availability of lipid during timesof need. Lipogenesis is promoted by insulin and, in lampreyand anurans, also by thyroid hormones. Lipolysis is promotedby a number of hormones, including prolactin, growth hormone,adrenocorticotropic hormone, corticosteroids, somatostatins,and thyroid hormones. The coordinate regulation of development-associatedchanges in lipid metabolism results from interactions amonghormones and other internal and environmental cues.