Review Mechanisms of thyroid hormone receptor action during development: Lessons from amphibian studies ☆ Alexis Grimaldi a , Nicolas Buisine a , Thomas Miller b , Yun-Bo Shi b , Laurent M. Sachs a, ⁎ a Muséum National d'Histoire Naturelle, Dépt. Régulation Développement et Diversité Moléculaire, UMR7221 CNRS, Evolution des Régulations Endocriniennes, Section on thyroid hormone receptor function and mechanism of action, 57 rue Cuvier, 75231 Paris cedex 05, France b Section on Molecular Morphogenesis, Program in Cellular Regulation and Metabolism, NICHD, NIH, Bldg. 18T, Rm. 106, Bethesda, MD 20892, USA abstract article info Article history: Received 10 January 2012 Received in revised form 28 March 2012 Accepted 21 April 2012 Available online xxxx Keywords: Thyroid hormone Transcriptional regulation Histone modification Chromatin remodeling Coregulator Amphibian metamorphosis Background: Thyroid hormone (TH) receptor (TR) plays critical roles in vertebrate development. However, the in vivo mechanism of TR action remains poorly explored. Scope of review: Frog metamorphosis is controlled by TH and mimics the postembryonic period in mammals when high levels of TH are also required. We review here some of the findings on the developmental func- tions of TH and TR and the associated mechanisms obtained from this model system. Major conclusion: A dual function model for TR in Anuran development was proposed over a decade ago. That is, unliganded TR recruits corepressors to TH response genes in premetamorphic tadpoles to repress these genes and prevent premature metamorphic changes. Subsequently, when TH becomes available, liganded TR recruits coactivators to activate these same genes, leading to metamorphic changes. Over the years, mo- lecular and genetic approaches have provided strong support for this model. Specifically, it has been shown that unliganded TR recruits histone deacetylase containing corepressor complexes during larval stages to control metamorphic timing, while liganded TR recruits multiple histone modifying and chromatin remodeling coactivator complexes during metamorphosis. These complexes can alter chromatin structure via nucleosome position alterations or eviction and histone modifications to contribute to the recruitment of transcriptional machinery and gene activation. General significance: The molecular mechanisms of TR action in vivo as revealed from studies on amphibian metamorphosis are very likely applicable to mammalian development as well. These findings provide a new perspective for understanding the diverse effects of TH in normal physiology and diseases caused by TH dysfunction. This article is part of a Special Issue entitled Thyroid hormone signalling. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Thyroid hormones (TH) regulate multiple developmental and physiological functions in vertebrates. At the cellular level, 3,5,3′ triiodothyronine (T 3 ), the active form of TH, controls cell metabolism, proliferation, and commitment to differentiation or apoptosis. TH is synthesized in the thyroid gland. This organ has attracted the atten- tion of physicians since antiquity. It was only 100 years ago that TH had begun to be characterized. In 1912, Friedrich Gudernatsch fed premetamorphic tadpoles with several horse organs and found that thyroid gland but none of the others could accelerate amphibian metamorphosis [1]. Amphibian development is a biphasic process. Embryonic stages and juvenile life are separated by a larval (tadpole) period that ends with metamorphosis. Metamorphosis is a switch that results in the reprogramming of the morphological and biochemical characteristics of nearly all tadpole organs, including de novo development (limbs), tissue remodeling (nervous system) and organ resorption (tail) [2]. These transformations involve apoptosis of larval cells and concurrent proliferation and differentiation of adult cell types. Amphibian metamorphosis bears strong similarities with the peri- natal (postembryonic) development in mammals at molecular and morphological levels [3]. First, both take place in a period when plas- ma TH levels peak during development. Second, both mammals and Biochimica et Biophysica Acta xxx (2012) xxx–xxx Abbreviations: TH, Thyroid hormone; TR, Thyroid hormone receptor; T 3 , 3,5,3′ triio- dothyronine; TRE, TH response element; DR, direct repeat; IR, inverted repeat or palin- drome; ER, everted repeat; RXR, retinoic acid X receptor; dp, dominant positive; dn, dominant negative; NCoR, Nuclear receptor CoRepressor; SMRT, Silencing Mediator for RAR and TR; ChIP, chromatin immunoprecipitation; HDAC, histone deacetylase; TBL1, transducin beta like protein 1; SRC, steroid receptor coactivator; CBP, p300/ CREB binding protein; CARM1, coactivator associated arginine methyltransferase 1; PRMT1, Protein arginine methyltransferase 1; DRIP, vitamin D receptor interacting pro- tein complex; TRAP, TR associated protein complex; ARC, activator recruited cofactor complex; BRG1, Brahma related gene 1; BAF57, BRG1 associated factor 57; HDM, his- tone demethylase; HAT, histone acetyltransferase; HMT, histone methyltransferase; ezh2, enhancer of zeste 2; H3, histone H3; H4, histone H4; Me2, Dimethyl; Me3, Trimethyl; K, Lysine; R, Arginine; X. laevis, Xenopus leavis; X. tropicalis, Xenopus tropicalis ☆ This article is part of a Special Issue entitled Thyroid hormone signalling. ⁎ Corresponding author at: UMR7221 CNRS, MNHN, CP 32, 7 rue Cuvier, 75231 Paris cedex 05, France. Tel.: +33 1 40 79 36 04; fax: +33 1 40 79 36 18. E-mail address: sachs@mnhn.fr (L.M. Sachs). BBAGEN-27226; No. of pages: 11; 4C: 3, 4, 6, 8 0304-4165/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2012.04.020 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen Please cite this article as: A. Grimaldi, et al., Mechanisms of thyroid hormone receptor action during development: Lessons from amphibian studies, Biochim. Biophys. Acta (2012), doi:10.1016/j.bbagen.2012.04.020