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
Source: PubMed


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.

13 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    General and Comparative Endocrinology 06/2014; 204. DOI:10.1016/j.ygcen.2014.05.030 · 2.47 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to determine if chronic exposure to the glyphosate-based herbicide VisionMax(®) affects the survival, development, growth, sex ratios and expression of specific genes involved in metamorphosis of wood frog tadpoles (Lithobates sylvaticus). We hypothesized that exposure to this herbicide will affect developmental rates by disrupting hormone pathways, sex ratios and/or gonadal morphology. Tadpoles were chronically exposed in the laboratory from Gosner developmental stage 25 to 42 to four different concentrations of VisionMax(®) (ranging from 0.021 to 2.9mg acid equivalents/L). Chronic exposures to VisionMax(®) had direct effects on the metamorphosis of L. sylvaticus tadpoles by decreasing development rates, however, there was a decrease in survival only in the group exposed to the highest dose of VisionMax(®) (2.9mga.e./L; from approximately 96% in the control group to 77% in the treatment group). There was a decrease in the number of tadpoles reaching metamorphic climax, from 78% in the control group to 42% in the VisionMax(®) (2.9mga.e./L) group, and a 7-day delay to reach metamorphic climax in the same treatment group. No effects of exposure on sex ratios or gonadal morphology were detected in tadpoles exposed to any of the concentrations of VisionMax(®) tested. Gene expression analyses in brain and tail tissues demonstrated that exposure to VisionMax(®) alters the expression of key genes involved in development. Results showed significant interaction (two-way ANOVA, P<0.05) between developmental Gosner stage and treatment in brain corticotropin-releasing factor, deiodinase type II (dio2) and glucocorticotiroid receptor (grII) and tail dio2 and grII. This demonstrates that mRNA levels may be differently affected by treatment depending on the developmental stage at which they are assessed. At the same time there was a clear dose-response effect for VisionMax(®) to increase thyroid hormone receptor β in tadpole brain (F(2,69)=3.475, P=0.037) and tail (F(2,69)=27.569, P<0.001), regardless of developmental stage. Interestingly, delays in development (or survival) were only observed in the group exposed to 2.9mga.e./L of VisionMax(®), suggesting that tadpoles need to be exposed to a "threshold" concentration of glyphosate-based herbicide to exhibit phenotypic observable effects. We suggest that the upregulation of genes that trigger metamorphosis following VisionMax(®) herbicide exposure might result from a compensatory response for the delays in development observed. Further studies are needed to determine if disruption of expression of these key genes leads to long-term effects when metamorphs reach adult stages.
    Aquatic Toxicology 05/2014; 154:278-290. DOI:10.1016/j.aquatox.2014.05.017 · 3.45 Impact Factor
  • Source
    • "As in mammals, the major circulating TH in amphibians is T4, which is converted to T3 in the peripheral tissues by D2 (Galton 1989; Becker et al. 1997). To test whether D2 activity is involved in the death of the TRa-transfected muscle cells that are induced by low levels of T4, we assessed the effect of the D2 inhibitor iopanoic acid on cell death. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During amphibian metamorphosis, a series of dynamic changes occur in a predetermined order. Hind limb morphogenesis begins in response to low levels of thyroid hormone (TH) in early prometamorphosis, but tail muscle cell death is delayed until climax, when TH levels are high. It takes about 20 days for tadpoles to grow from early prometamorphosis to climax. To study the molecular basis of the timing of tissue-specific transformations, we introduced thyroid hormone receptor (TR) expression constructs into tail muscle cells of Xenopus tadpoles. The TR-transfected tail muscle cells died upon exposure to a low level of thyroxine (T4). This cell death was suggested to be mediated by type 2 iodothyronine deiodinase (D2) that converts T4 to T3-the more active form of TH. D2 mRNA was induced in the TR-overexpressing cells by low levels of TH. D2 promoter contains a TH-response element (TRE) with a lower affinity for TR. These results show that the TR transfection confers the ability to respond to physiological concentrations of TH at early prometamorphosis to tail muscle cells through D2 activity and promotes TH signaling. We propose the positive feedback loop model to amplify the cell's ability to respond to low levels of T4.
    Genes to Cells 06/2012; 17(8):645-59. DOI:10.1111/j.1365-2443.2012.01614.x · 2.81 Impact Factor
Show more

Similar Publications


13 Reads