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      Evolutionary Conservation of Thyroid Hormone Receptor and Deiodinase Expression Dynamics in ovo in a Direct-Developing Frog, Eleutherodactylus coqui

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          Direct development is a reproductive mode in amphibians that has evolved independently from the ancestral biphasic life history in at least a dozen anuran lineages. Most direct-developing frogs, including the Puerto Rican coquí, Eleutherodactylus coqui, lack a free-living aquatic larva and instead hatch from terrestrial eggs as miniature adults. Their embryonic development includes the transient formation of many larval-specific features and the formation of adult-specific features that typically form postembryonically—during metamorphosis—in indirect-developing frogs. We found that pre-hatching developmental patterns of thyroid hormone receptors alpha ( thra) and beta ( thrb) and deiodinases type II ( dio2) and type III ( dio3) mRNAs in E. coqui limb and tail are conserved relative to those seen during metamorphosis in indirect-developing frogs. Additionally, thra, thrb, and dio2 mRNAs are expressed in the limb before formation of the embryonic thyroid gland. Liquid-chromatography mass-spectrometry revealed that maternally derived thyroid hormone is present throughout early embryogenesis, including stages of digit formation that occur prior to the increase in embryonically produced thyroid hormone. Eleutherodactylus coqui embryos take up much less 3,5,3′-triiodothyronine (T 3) from the environment compared with X. tropicalis tadpoles. However, E. coqui tissue explants mount robust and direct gene expression responses to exogenous T 3 similar to those seen in metamorphosing species. The presence of key components of the thyroid axis in the limb and the ability of limb tissue to respond to T 3 suggest that thyroid hormone-mediated limb development may begin prior to thyroid gland formation. Thyroid hormone-dependent limb development and tail resorption characteristic of metamorphosis in indirect-developing anurans are evolutionarily conserved, but they occur instead in ovo in E. coqui.

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          Thyroid hormone receptors in brain development and function.

           Juan Bernal (2007)
          Thyroid hormones are important during development of the mammalian brain, acting on migration and differentiation of neural cells, synaptogenesis, and myelination. The actions of thyroid hormones are mediated through nuclear thyroid hormone receptors (TRs) and regulation of gene expression. The purpose of this article is to review the role of TRs in brain maturation. In developing humans maternal and fetal thyroid glands provide thyroid hormones to the fetal brain, but the timing of receptor ontogeny agrees with clinical data on the importance of the maternal thyroid gland before midgestation. Several TR isoforms, which are encoded by the THRA and THRB genes, are expressed in the brain, with the most common being TRalpha1. Deletion of TRalpha1 in rodents is not, however, equivalent to hormone deprivation and, paradoxically, even prevents the effects of hypothyroidism. Unliganded receptor activity is, therefore, probably an important factor in causing the harmful effects of hypothyroidism. Accordingly, expression of a mutant receptor with impaired triiodothyronine (T(3)) binding and dominant negative activity affected cerebellar development and motor performance. TRs are also involved in adult brain function. TRalpha1 deletion, or expression of a dominant negative mutant receptor, induces consistent behavioral changes in adult mice, leading to severe anxiety and morphological changes in the hippocampus.
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            Molecular and developmental analyses of thyroid hormone receptor function in Xenopus laevis, the African clawed frog.

            The current review focuses on the molecular mechanisms and developmental roles of thyroid hormone receptors (TRs) in gene regulation and metamorphosis in Xenopus laevis and discusses implications for TR function in vertebrate development and diversity. Questions addressed are: (1) what are the molecular mechanisms of gene regulation by TR, (2) what are the developmental roles of TR in mediating the thyroid hormone (TH) signal, (3) what are the roles of the different TR isoforms, and (4) how do changes in these molecular and developmental mechanisms affect evolution? Even though detailed knowledge of molecular mechanisms of TR-mediated gene regulation is available from in vitro studies, relatively little is known about how TR functions in development in vivo. Studies on TR function during frog metamorphosis are leading the way toward bridging the gap between in vitro and in vivo studies. In particular, a dual function model for the role of TR in metamorphosis has been proposed and investigated. In this model, TRs repress genes allowing tadpole growth in the absence of TH during premetamorphosis and activate genes important for metamorphosis when TH is present. Despite the lack of metamorphosis in most other vertebrates, TR has important functions in development across vertebrates. The underlying molecular mechanisms of TR in gene regulation are conserved through evolution, so other mechanisms involving TH-target genes and TH tissue-sensitivity and dependence underlie differences in role of TR across vertebrates. Continued analysis of molecular and developmental roles of TR in X. laevis will provide the basis for understanding how TR functions in gene regulation in vivo across vertebrates and how TR is involved in the generation of evolutionary diversity.
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              The role of thyroid hormone in zebrafish and axolotl development.

              Exogenous thyroid hormone (TH) induces premature differentiation of the zebrafish pectoral fins, which are analogous to the forelimbs of tetrapods. It accelerates the growth of the pelvic fins but not precociously. Goitrogens, which are chemical inhibitors of TH synthesis by the thyroid gland, inhibit the transition from larva to juvenile fish including the formation of scales, and pigment pattern; they stunt the growth of both pectoral and pelvic paired fins. Inhibition by goitrogens is rescued by the simultaneous addition of thyroxine. The effect of adding TH to the rearing water of the postembryonic Mexican axolotl was reinvestigated under conditions that permit continued growth and development. In addition to morphological changes that have been described, TH greatly stimulates axolotl limb growth causing the resulting larva to be proportioned as an adult in about two months. This study extends the known evolutionary relatedness of tetrapod limbs and fish fins to include the TH stimulation of salamander limb and zebrafish fin growth, and suggests that TH is required to complete the life cycle of a typical bony fish and a salamander at the same developmental stage that it controls anuran and flounder metamorphosis.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                24 May 2019
                : 10
                1Department of Organismic and Evolutionary Biology, and Museum of Comparative Zoology, Harvard University , Cambridge, MA, United States
                2Departments of Molecular, Cellular and Developmental Biology, and Ecology and Evolutionary Biology, University of Michigan , Ann Arbor, MI, United States
                Author notes

                Edited by: Marco António Campinho, Center of Marine Sciences (CCMAR), Portugal

                Reviewed by: Paula Duarte-Guterman, University of British Columbia, Canada; Salvatore Benvenga, University of Messina, Italy

                *Correspondence: Mara Laslo mlaslo@ 123456g.harvard.edu

                This article was submitted to Thyroid Endocrinology, a section of the journal Frontiers in Endocrinology

                Copyright © 2019 Laslo, Denver and Hanken.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 3, Equations: 0, References: 66, Pages: 14, Words: 10157
                Funded by: Sigma Delta Epsilon-Graduate Women in Science 10.13039/100005231
                Original Research


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