The type 2 and Type 3 iodothyronine deiodinase play important roles in coordinating development in Rana catesbeiana tadpoles
Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756-0001, USA.Endocrinology (Impact Factor: 4.5). 08/1997; 138(7):2989-97. DOI: 10.1210/en.138.7.2989
In developing Rana catesbeiana tadpoles, the timing of the thyroid hormone (TH)-dependent metamorphic responses varies markedly among tissues. Yet at any one time these tissues are exposed to the same plasma concentration of TH, suggesting that TH action is regulated in part at the level of the peripheral tissues. A major factor in TH action is the intracellular level of the active TH, T3. This level is dependent not only on the plasma concentration of TH (mostly T4) but also on the intracellular activities of the type 2 5'-deiodinase (D2) and the type 3 5-deiodinase (D3), which are responsible, respectively, for generating and degrading T3. (D1 is not present in this species.) To determine whether differential expression of D2 and D3 among tissues could be a significant factor in the coordination of metamorphic events, the ontogenic profiles of the two enzyme activities and corresponding messenger RNA levels in most tissues of R. catesbeiana tadpoles have been documented. The profiles of D2 expression in tail, hindlimb, forelimb, intestine, skin, and eye differed markedly at both activity and messenger RNA levels, but it was notable that expression was invariably highest in a given tissue at the time of its major metamorphic change. D2 expression was very low in brain and heart and did not vary during development. D2 was not expressed in liver, kidney, or red blood cells. With the exception of red blood cells, D3 expression was detected in all tissues studied. Furthermore, it was evident that in tissues that expressed both deiodinase genes, the two expression profiles were comparable, indicating a potential for tight control of intracellular T3 levels. Direct evidence of the importance of the intracellular conversion of T4 to T3 for TH-dependent metamorphic events was obtained in tadpoles in which endogenous TH synthesis was blocked with methimazole, and the activities of D2 and D3 were inhibited by iopanoic acid. This treatment inhibited metamorphosis. The inhibition could be overcome by the concomitant administration of replacement levels of T3, but not T4. These results strongly support the view that coordinated development in amphibia depends in part on the tissue-specific expression patterns of the D2 and D3 genes, which ensure that the requisite level of intracellular T3 is attained in a given tissue, regardless of the current level of circulating TH, at the appropriate stage of metamorphosis.
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- "In flatfish, the pelagic " round " larvae becomes a " flat " benthic juvenile in synchrony with the migration of one eye to the opposite side of the head. Thyroid hormones (THs) are the necessary and essential factors regulating post-embryonic metamorphosis (revised in Denver, 2013; Power et al., 2008) and exert their effect through a whole-body and tissue/ cell specific manner in both anurans and flatfishes (Becker et al., 1997; Campinho et al., 2007a Campinho et al., , 2007b Campinho et al., , 2012a Denver, 1997; Denver et al., 2009; Huang et al., 1999; Inui and Miwa, 1985; Inui et al., 1989 Inui et al., , 1995 Kaneko et al., 2005; Lema et al., 2009; Manchado et al., 2008; Manzon and Denver, 2004; Okada et al., 2007). In contrast to mammals where thyrotropin-releasing hormone (trh) acts as the hypothalamic regulator of the hypothalamus–pituitary–thyroid (HPT) axis (Fekete and Lechan, 2007; Fliers et al., 2006), in anurans, reptiles and birds development corticotropin releasing hormone (crh) has a more prominent role in regulating thyrotropin (tshb) secretion and T4 serum levels (De Groef et al., 2006; Denver, 2013). "
ABSTRACT: Anuran and flatfish metamorphosis are tightly regulated by thyroid hormones that are the necessary and sufficient factors that drive this developmental event. In the present study whole mount in situ hybridisation (WISH) and quantitative PCR in sole is used to explore the central regulation of flatfish metamorphosis. Central regulation of the thyroid in vertebrates is mediated by the hypothalamus-pituitary-thyroid (HPT) axis. Teleosts diverge from other vertebrates as hypothalamic regulation in the HPT axis is proposed to be through hypothalamic inhibition although the regulatory factor remains enigmatic. The dynamics of the HPT axis during sole metamorphosis revealed integration between the activity of the thyrotrophes in the pituitary and the thyroid follicles. No evidence was found supporting a role for thyroid releasing hormone (trh) or corticotrophin releasing hormone (crh) in hypothalamic control of TH production during sole metamorphosis. Intriguingly the results of the present study suggest that neither hypothalamic trh nor crh expression changes during sole metamorphosis and raises questions about the role of these factors and the hypothalamus in regulation of thyrotrophs. Copyright © 2014. Published by Elsevier Ireland Ltd.
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- "Likewise, correlations between intestinal remodeling and the expression patterns of PmTRs and PmRXRs are observed during lamprey metamorphosis (Youson and Connelly, 1978; Youson and Horbert, 1982; Eales et al., 2000). The role of TH and TH deiodinases in the regulation of intestinal remodeling in amphibians is well established (Ishizuya-Oka et al., 2010; Becker et al., 1997; Brown, 2005; Brown and Cai, 2007). Future work should identify and investigate TH responsive genes in lampreys that are associated with lipid metabolism and intestinal remodeling. "
ABSTRACT: Sea lampreys (Petromyzon marinus) are members of the ancient class Agnatha and undergo a metamorphosis that transforms blind, sedentary, filter-feeding larvae into free-swimming, parasitic juveniles. Thyroid hormones (THs) appear to be important for lamprey metamorphosis, however, serum TH concentrations are elevated in the larval phase, decline rapidly during early metamorphosis and remain low until metamorphosis is complete; these TH fluctuations are contrary to those of other metamorphosing vertebrates. Moreover, thyroid hormone synthesis inhibitors (goitrogens) induce precocious metamorphosis and exogenous TH treatments disrupt natural metamorphosis in P. marinus. Given that THs exert their effects by binding to TH nuclear receptors (TRs) that often act as heterodimers with retinoid X receptors (RXRs), we cloned and characterized these receptors from P. marinus and examined their expression during metamorphosis. Two TRs (PmTR1 and PmTR2) and three RXRs (PmRXRs) were isolated from P. marinus cDNA. Phylogenetic analyses group the PmTRs together on a branch prior to the gnathostome TRα/β split. The three RXRs also group together, but our data indicated that these transcripts are most likely either allelic variants of the same gene locus, or the products of a lamprey-specific duplication event. Importantly, these P. marinus receptors more closely resemble vertebrate as opposed to invertebrate chordate receptors. Functional analysis revealed that PmTR1 and PmTR2 can activate transcription of TH-responsive genes when treated with nanomolar concentrations of TH and they have distinct pharmacological profiles reminiscent of vertebrate TRβ and TRα, respectively. Also similar to other metamorphosing vertebrates, expression patterns of the PmTRs during lamprey metamorphosis suggest that PmTR1 has a dynamic, tissue-specific expression pattern that correlates with tissue morphogenesis and biochemical changes and PmTR2 has a more uniform expression pattern. This TR expression data suggests that THs, either directly or via a metabolite, may function to positively modulate changes at the tissue or organ levels during lamprey metamorphosis. Collectively the results presented herein support the hypothesis that THs have a dual functional role in the lamprey life cycle whereby high levels promote larval feeding, growth and lipogenesis and low levels promote metamorphosis.
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- "Deiodinase enzymes (Dios) are responsible for the step-wise removal of iodine from iodinated thyronines, resulting in metabolites with increased or decreased biological activity (Orozco et al., 2012). Three isoforms of deiodinase enzyme (Dio1, Dio2 and Dio3) coordinate tissuespecific metabolism of TH during metamorphosis (Becker et al., 1997; Galton, 1992; Kawahara et al., 1999; Kuiper et al., 2006; Sutija and Joss, 2006). While the role of Dio1 in metamorphosis remains unclear, it can be generalized that Dio2 is critical because it converts T 4 into the more active form T 3 , whereas Dio3 converts T4 into the biologically inactive reverse T 3 (rT3) and T3 to biologically inactive T2. "
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