BBA - General Subjects (v.1830, #7)

Thyroid hormone signaling by Douglas Forrest; Theo J. Visser (3859).

The road to nuclear receptors of thyroid hormone by Jamshed R. Tata (3860-3866).
Early studies on the mechanism of action of thyroid hormone (TH) measured changes in enzyme activities following the addition of l-thyroxine (T4) and 3, 3′, 5-triiodothyronine (T3) to tissue extracts and purified enzymes.As techniques for isolation of mitochondria, ribosomes, nuclei and chromatin, were increasingly refined, it became possible to study complex cellular processes, such as oxidative phosphorylation, protein synthesis, transcription and chromosomal structure. Uncoupling of oxidative phosphorylation and direct action on protein synthesis as mechanisms of action of TH, proposed in the 1950s and 1960s, were found to be untenable as mechanisms of physiological action because of inappropriate experimental conditions.Several findings in the 1960s and 1970s, mainly 1) that near-physiological doses of T3 stimulated transcription measured in vivo or in nuclei isolated from tissues of rats and frog tadpoles, 2) the inhibition of hormone action by inhibitors of transcription and 3) the rapid and almost identical kinetics of accumulation of labelled hormone and RNA synthesis in target cell nuclei, pointed to the cell nucleus as a major site of its action. The application of technologies of recombinant DNA, gene cloning and DNA sequencing in the mid-1980s allowed the identification and understanding of the structure and function of nuclear receptors of TH.This review traces the road leading to the nuclear receptors of thyroid hormone, thus explaining how the hormone influences gene expression. It also illustrates the importance of how new concepts originate from the progression of technological innovations. This article is part of a Special Issue entitled Thyroid hormone signalling.► Early biochemical studies of the mechanism of TH action in mammals and amphibians. ► Transcription and nucleus established as major targets of TH in 1960s and 1970s. ► Nuclear receptors of TH identified in 1986 as cellular homologues of oncogene cErbA. ► Structure and function of nuclear receptors are key to understanding of TH action.
Keywords: Triiodothyronine; Hormone action; Oxidative phosphorylation; Amphibian metamorphosis: transcription; Nuclear receptor;

Mediator is an evolutionarily conserved multisubunit complex that plays an essential regulatory role in eukaryotic transcription of protein-encoding genes. The human complex was first isolated as a transcriptional coactivator bound to the thyroid hormone receptor (TR) and has since been shown to play a key coregulatory role for a broad range of nuclear hormone receptors (NRs) as well as other signal-activated transcription factors.We provide a general overview of Mediator structure and function, summarize the mechanisms by which Mediator is targeted to NRs, and outline recent evidence revealing Mediator as a regulatory axis for other distinct coregulatory factors, chromatin modifying enzymes and cellular signal transduction pathways.Besides serving as a functional interface with the RNA polymerase II basal transcription machinery, Mediator plays a more versatile role in regulating transcription including the ability to: a) facilitate gene-specific chromatin looping events; b) coordinate chromatin modification events with preinitiation complex assembly; and c) regulate critical steps that occur during transcriptional elongation. The variably associated MED1 subunit continues to emerge as a pivotal player in Mediator function, not only as the primary interaction site for NRs, but also as a crucial interaction hub for other coregulatory factors, and as an important regulatory target for signal-activated kinases.Mediator plays an integral coregulatory role at NR target genes by functionally interacting with the basal transcription apparatus and by coordinating the action of chromatin modifying enzymes and transcription elongation factors. This article is part of a Special Issue entitled Thyroid hormone signalling.► MED1 interacts with NRs, gene-specific activators and other coregulatory factors. ► MED1 is a regulatory target for MAPK-ERK. ► Mediator involvement in gene-specific chromatin looping. ► Mediator coordination of chromatin modification events. ► Mediator involvement in transcriptional elongation.
Keywords: Thyroid hormone receptor; Transcription; Nuclear receptor; Coactivator; Phosphorylation;

The in vivo role of nuclear receptor corepressors in thyroid hormone action by Inna Astapova; Anthony N. Hollenberg (3876-3881).
The thyroid hormone receptor (TR) isoforms interact with a variety of coregulators depending upon the availability of T3 to mediate their transcriptional effect. Classically, in the absence of ligand, the TRs recruit the nuclear corepressors, NCoR and SMRT, to mediate transcriptional repression on positively regulated TR target genes. However, new insight into the roles of NCoR and SMRT using in vivo models have better defined the role of nuclear corepressors both in the absence and presence of T3.This review will place the variety of in vivo nuclear corepressor mouse models developed to date in context of thyroid hormone action. Based on these models, we will also discuss how corepressor availability together with the levels of endogenous nuclear receptor ligands including T3 controls multiple signaling pathways.Nuclear corepressors mediate repression of positive TR targets in the absence of T3 in vivo. Even more importantly they attenuate activation of these targets at the normal physiological levels of ligands by TR and other nuclear receptors. While the role of corepressors in the regulation of negative TR targets and HPT axis remains poorly understood, lack of corepressor recruitment to TR in the animals leads to a compensatory change in the set point of HPT axis that allows to balance the increased sensitivity to T3 action in other tissues.Available data indicate that targeting specific interactions between corepressors and TR or other nuclear receptors presents a new therapeutic strategy for endocrine and metabolic disorders. This article is part of a Special Issue entitled Thyroid hormone signalling.► Mouse models allow assessment of the role of CoRs in NR signaling. ► CoRs mediate repression of positive targets by TR in the absence of T3. ► CoRs play a role in establishing a set point of HPT axis. ► CoRs attenuate transcriptional activity of NRs in the presence of ligands. ► CoR might be new drug targets for endocrine and metabolic disorders.
Keywords: Thyroid hormone; Corepressor; T3; Transcription;

Mechanisms of thyroid hormone receptor action during development: Lessons from amphibian studies by Alexis Grimaldi; Nicolas Buisine; Thomas Miller; Yun-Bo Shi; Laurent M. Sachs (3882-3892).
Thyroid hormone (TH) receptor (TR) plays critical roles in vertebrate development. However, the in vivo mechanism of TR action remains poorly explored.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 functions of TH and TR and the associated mechanisms obtained from this model system.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, molecular 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.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.► Thyroid hormones induce metamorphosis that mimics the perinatal period in mammals. ► Amphibians provide an excellent model to analyze thyroid hormone receptor action. ► Thyroid hormone receptors act on gene expression through coregulators recruitment. ► Thyroid hormone receptor can change the chromatin structure and histone modifications. ► A model that highlights the diversity of thyroid hormone effects could be proposed.
Keywords: Thyroid hormone; Transcriptional regulation; Histone modification; Chromatin remodeling; Coregulator; Amphibian metamorphosis;

The transcriptional activity of the thyroid hormone receptors is modulated by the ligand, T3, but they have also activity as aporeceptors, in the unliganded state. Aporeceptor activity is thought to contribute to the severity of profound hypothyroidism. During development thyroid hormone receptors are expressed before onset of thyroid gland function and are present therefore in many tissues mainly as aporeceptors. The question we address is whether thyroid hormone aporeceptors are involved in physiological and/or developmental processes.The scope of this article is to review the evidence for a role of thyroid hormone aporeceptors in physiology and development. Related to this topic is the activity of mutant receptors unable to bind hormone. These receptors usually have dominant negative activity. This review focuses on the wild type receptors, and does not discuss the properties of mutant receptors.Unliganded thyroid hormone receptors influence the timing and control certain aspects of amphibian pre-metamorphosis. In mammals they are likely to influence maturational processes in the brain and other organs before onset of thyroid gland function. Expression of types 2 and 3 deiodinases which control the local tissue concentration of T3 regulates the fractional receptor occupancy and therefore the relative proportion of aporeceptors. This article is part of a Special Issue entitled Thyroid hormone signalling.►Uliganded TRβ1 is involved in upregulation of TRH in hypothyroidism. ►Unliganded TRα controls some aspects of pre-metamorphosis. ►Unliganded TRα1 is involved in the timing of K+ channel expression in the cochlea. ►Apo- to holo-receptor switch influences gene expression during heart development. ►Induction of the Klf2 transcription factor in lung and pneumocyte I maturation requires unliganded TR.
Keywords: Thyroid hormones; Nuclear receptors; Metamorphosis; Development; Hypothyroidism; Aporeceptor;

Thyroid hormone receptors TRα1, TRβ1 and TRβ2 are broadly expressed and exert a pleiotropic influence on many developmental and homeostatic processes. Extensive genetic studies in mice precisely defined their respective function.Mouse genetics support a balanced contribution of expression pattern and receptor intrinsic properties in defining the receptor respective functions. The molecular mechanisms sustaining cell specific response remain hypothetical and based on studies performed with other nuclear receptors.The isoform-specificity and cell-specificity questions have many implications for clinical research, drug development, and endocrine disruptor studies. This article is part of a Special Issue entitled Thyroid hormone signalling.► Genetic data indicate different functions for thyroid hormone receptor isotypes. ► Combination of knock-out suggest functional redundancy between the isotypes. ► Isotype specific functions exist in some cell types. ► Thyroid hormone target genes differ, depending on cell type and species. ► Synthetic ligands and environmental pollutants modify thyroid hormone signaling.
Keywords: Thyroid hormone; Nuclear receptor; Mouse genetics;

Thyroid hormone receptors, cell growth and differentiation by Angel Pascual; Ana Aranda (3908-3916).
Tissue homeostasis depends on the balance between cell proliferation and differentiation. Thyroid hormones (THs), through binding to their nuclear receptors, can regulate the expression of many genes involved in cell cycle control and cellular differentiation. This can occur by direct transcriptional regulation or by modulation of the activity of different signaling pathways.In this review we will summarize the role of the different receptor isoforms in growth and maturation of selected tissues and organs. We will focus on mammalian tissues, and therefore we will not address the fundamental role of the THs during amphibian metamorphosis.The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status. Both during development and in the adult, stem cells are essential for proper organ formation, maintenance and regeneration. Recent evidence suggests that some of the actions of the thyroid hormone receptors could be secondary to regulation of stem/progenitor cell function. Here we will also include the latest knowledge on the role of these receptors in proliferation and differentiation of embryonic and adult stem cells.The thyroid hormone receptors are potent regulators of proliferation and differentiation of many cell types. This can explain the important role of the thyroid hormones and their receptors in key processes such as growth, development, tissue homeostasis or cancer. This article is part of a Special Issue entitled Thyroid hormone signalling.► The thyroid hormone receptors regulate cell proliferation and differentiation. ► These receptors can both promote and inhibit proliferation. ► Their effects are time and cell context dependent. ► They can regulate transcription directly or modulate activity of other pathways. ► The thyroid hormone receptors can affect stem/progenitor cell function.
Keywords: Thyroid hormone receptor; Gene expression; Tissue homeostasis; Progenitor/stem cell;

Thyroid hormone's action on progenitor/stem cell biology: New challenge for a classic hormone? by Maria Sirakov; Seham Skah; Julien Nadjar; Michelina Plateroti (3917-3927).
Thyroid hormones are involved in developmental and homeostatic processes in several tissues. Their action results in different outcomes depending on the developmental stage, tissue and/or cellular context. Interestingly, their pleiotropic roles are conserved across vertebrates. It is largely documented that thyroid hormones act via nuclear receptors, the TRs, which are transcription factors and whose activity can be modulated by the local availability of the hormone T3. In the “classical view”, the T3-induced physiological response depends on the expression of specific TR isoforms and the iodothyronine deiodinase selenoenzymes that control the local level of T3, thus TR activity.Recent data have clearly established that the functionality of TRs is coordinated and integrated with other signaling pathways, specifically at the level of stem/progenitor cell populations. Here, we summarize these data and propose a new and intriguing role for thyroid hormones in two selected examples.In the intestinal epithelium and the retina, TRα1 and TRβ2 are expressed at the level of the precursors where they induce cell proliferation and differentiation, respectively. Moreover, these different functions result from the integration of the hormone signal with other intrinsic pathways, which play a fundamental role in progenitor/stem cell physiology.Taken together, the interaction of TRs with other signaling pathways, specifically in stem/progenitor cells, is a new concept that may have biological relevance in therapeutic approaches aimed to target stem cells such as tissue engineering and cancer. This article is part of a Special Issue entitled Thyroid hormone signalling.► The thyroid hormones and the nuclear receptors TR control the developmental and the homeostatic processes in several tissues. ► The intestine and the retina are organ targets of the thyroid hormones and the TRs. ► The action of the thyroid hormones and TRs is coordinated and integrated with other signaling pathways. ► New data also describe their involvement in gut epithelial stem cell physiology.
Keywords: Intestine; Retina; Thyroid hormone; Thyroid hormone receptor TR; Stem cells;

Thyroid hormone receptors and cancer by Won Gu Kim; Sheue-yann Cheng (3928-3936).
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in development, growth, and differentiation. The THRA and THRB genes encode several TR isoforms that express in a tissue- and development-dependent manner. In the past decades, a significant advance has been made in the understanding of TR actions in maintaining normal cellular functions. However, the roles of TRs in human cancer are less well understood. The reduced expression of TRs because of hypermethylation, or deletion of TR genes found in human cancers suggests that TRs could function as tumor suppressors. A close association of somatic mutations of TRs with human cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation.In line with the findings from association studies in human cancers, mice deficient in total functional TRs (Thra1 −/− Thrb −/− mice) or with a targeted homozygous mutation of the Thrb gene (denoted PV; Thrb PV/PV mice) spontaneously develop metastatic thyroid carcinoma. This review will examine the evidence learned from these genetically engineered mice that provided strong evidence to support the critical role of TRs in human cancer.Loss of normal functions of TR by deletion or by mutations could contribute to cancer development, progression and metastasis.Novel mechanistic insights are revealed in how aberrant TR activities lead to carcinogenesis. Mouse models of thyroid cancer provide opportunities to identify molecular targets as potential treatment modalities. This article is part of a Special Issue entitled Thyroid hormone signalling.► Mutations of thyroid hormone receptors (TRs) are associated with human cancers. ► Loss of TR normal functions by deletion or mutations contributes to cancer development. ► Mice harboring a homozygous mutation of TRβ spontaneously develop thyroid cancer. ► Nuclear and extra-nuclear actions of a TRβ mutant mediate thyroid carcinogenesis. ► Mouse models of thyroid cancer allow uncovering novel molecular targets for treatment.
Keywords: Thyroid hormone receptor mutant; Thyroid cancer; Phosphatidylinositol 3 kinase; Src kinase; β-Catenin; Mouse model;

The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation by Monica Dentice; Alessandro Marsili; AnnMarie Zavacki; P. Reed Larsen; Domenico Salvatore (3937-3945).
Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenodeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenodeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of deiodinases in specific cell types are not known, many important regulatory factors have been deciphered.This review provides striking examples from the recent literature illustrating how the expression of D2 and D3 is finely tuned during maturation of different organs, and how their action play a critical role in different settings to control intracellular T3 availability.Emerging evidence indicates that in various cell contexts, D2 and D3 are expressed in a dynamic balance, in which the expression of one enzyme is coordinately regulated with that of the other to tightly control intracellular T3 levels commensurate with cell requirements at that time.Deiodinases control TH action in a precise spatio-temporal fashion thereby providing a novel mechanism for the local paracrine and autocrine regulation of TH action. This remarkable tissue-specific regulation of intracellular thyroid status remains hidden due to the maintenance of constant circulating TH concentrations by the hypothalamic–pituitary–thyroid axis. This article is part of a Special Issue entitled Thyroid hormone signalling.► Deiodinases contribute to the control of TH availability in different cell types. ► Deiodinase actions are part of the TH-mediated control of differentiation. ► Deiodinases are critical in cochlear and retinal maturation in pre/post-natal life. ► In muscle cells, deiodinases are required for myogenesis and muscle regeneration.
Keywords: Thyroid hormone; Deiodinase; Cellular differentiation;

In recent years, findings in a number of animal and human models have ignited renewed interest in the type 3 deiodinase (D3), the main enzyme responsible for the inactivation of thyroid hormones. The induction of D3 in models of illness and injury has raised critical questions about the physiological significance of reduced thyroid hormone availability in those states. Phenotypes in transgenic mice lacking this enzyme also point to important developmental roles for D3. A critical determinant of D3 expression is genomic imprinting, an epigenetic phenomenon that regulates a small number of dosage-critical genes in the mammalian genome. The D3 gene (Dio3) is imprinted and preferentially expressed from one of the alleles in most tissues.In the context of the physiological significance of D3 and the characteristics and purported origins of genomic imprinting, we review the current knowledge about the epigenetic mechanisms specifying gene dosage in the Dio3 locus.Altered Dio3 dosage is detrimental to development, suggesting that the level of thyroid hormone action needs to be exquisitely tailored in a timely fashion to the requirements of particular tissues. An appropriate Dio3 dosage is the result of the coordinated action of certain genomic elements and epigenetic marks in the Dlk1-Dio3 domain.The imprinting of Dio3 prompts intriguing questions about why the level of thyroid hormone signaling should be regulated in this rare epigenetic manner, and to what extent altered Dio3 expression due to aberrant imprinting may be implicated in human conditions. This article is part of a Special Issue entitled Thyroid hormone signalling.► The type 3 deiodinase inactivates thyroid hormones thus limiting their action. ► D3 plays important roles during development and in adult physiology. ► The D3 gene is imprinted and preferentially expressed from the paternal allele. ► Dlk1-Dio3 locus genomic elements and epigenetic marks direct Dio3 allelic expression. ► Altered imprinted gene dosage in the Dlk1-Dio3 cluster causes abnormal phenotypes.
Keywords: Genomic imprinting; Type 3 deiodinase; Dio3; Thyroid hormone; Mouse chromosome 12; Uniparental disomy of chromosome 14;

Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling by Rafael Arrojo e Drigo; Tatiana L. Fonseca; Joao Pedro Saar Werneck-de-Castro; Antonio C. Bianco (3956-3964).
Thyroid hormone signaling is critical for development, growth and metabolic control in vertebrates. Although serum concentration of thyroid hormone is remarkable stable, deiodinases modulate thyroid hormone signaling on a time- and cell-specific fashion by controlling the activation and inactivation of thyroid hormone.This review covers the recent advances in D2 biology, a member of the iodothyronine deiodinase family, thioredoxin fold‐containing selenoenzymes that modify thyroid hormone signaling in a time- and cell-specific manner.D2-catalyzed T3 production increases thyroid hormone signaling whereas blocking D2 activity or disruption of the Dio2 gene leads to a state of localized hypothyroidism. D2 expression is regulated by different developmental, metabolic or environmental cues such as the hedgehog pathway, the adrenergic- and the TGR5-activated cAMP pathway, by xenobiotic molecules such as flavonols and by stress in the endoplasmic reticulum, which specifically reduces de novo synthesis of D2 via an eIF2a-mediated mechanism. Thus, D2 plays a central role in important physiological processes such as determining T3 content in developing tissues and in the adult brain, and promoting adaptive thermogenesis in brown adipose tissue. Notably, D2 is critical in the T4-mediated negative feed-back at the pituitary and hypothalamic levels, whereby T4 inhibits TSH and TRH expression, respectively. Notably, ubiquitination is a major step in the control of D2 activity, whereby T4 binding to and/or T4 catalysis triggers D2 inactivation by ubiquitination that is mediated by the E3 ubiquitin ligases WSB-1 and/or TEB4. Ubiquitinated D2 can be either targeted to proteasomal degradation or reactivated by deubiquitination, a process that is mediated by the deubiquitinases USP20/33 and is important in adaptive thermogenesis.Here we review the recent advances in the understanding of D2 biology focusing on the mechanisms that regulate its expression and their biological significance in metabolically relevant tissues. This article is part of a Special Issue entitled Thyroid hormone signalling.► Presentation of deiodinase-dependent thyroid hormone action ► Discussion of how D2 mediates T3 signaling and its regulation ► Physiological contribution of D2 to critical processes, such as control of basal metabolic rate ► New insights on D2's role in regulating the TSH-feedback mechanism
Keywords: Thyroid hormone; Deiodinase; Metabolism; Selenoprotein;

Function of thyroid hormone transporters in the central nervous system by Ulrich Schweizer; Josef Köhrle (3965-3973).
Iodothyronines are charged amino acid derivatives that cannot passively cross a phospholipid bilayer. Transport of thyroid hormones across plasma membranes is mediated by integral membrane proteins belonging to several gene families. These transporters therefore allow or limit access of thyroid hormones into brain. Since thyroid hormones are essential for brain development and cell differentiation, it is expected that genetic deficiency of such transporters would result in neurodevelopmental derangements.We introduce concepts of thyroid hormone transport into the brain and into brain cells. Important thyroid hormone transmembrane transporters are presented along with their expression patterns in different brain cell types. A focus is placed on monocarboxylate transporter 8 (MCT8) which has been identified as an essential thyroid hormone transporter in humans. Mutations in MCT8 underlie one of the first described X-linked mental retardation syndromes, the Allan–Herndon–Dudley syndrome.Thyroid hormone transporter molecules are expressed in a developmental and cell type-specific pattern. Any thyroid hormone molecule has to cross consecutively the luminal and abluminal membranes of the capillary endothelium, enter astrocytic foot processes, and leave the astrocyte through the plasma membrane to finally cross another plasma membrane on its way towards its target nucleus.We can expect more transporters being involved in or contributing to in neurodevelopmental or neuropsychiatric disease. Due to their expression in cellular components regulating the hypothalamus–pituitary–thyroid axis, mutations and polymorphisms are expected to impact on negative feedback regulation and hormonal setpoints. This article is part of a Special Issue entitled Thyroid hormone signalling.► Brain development and function depend on thyroid hormones. ► Thyroid hormones need plasma membrane transporters to enter cells. ► Different brain cell types express different sets of transporter molecules. ► Mutation of thyroid hormone transporter MCT8 leads to mental retardation.
Keywords: Brain; Neuron; Astrocyte; Blood–brain-barrier; Allan–Herndon–Dudley syndrome;

As a prerequisite for thyroid hormone (TH) metabolism and action TH has to be transported into cells where TH deiodinases and receptors are located. The trans-membrane passage of TH is facilitated by TH transporters of which the monocarboxylate transporter MCT8 has been most intensively studied. Inactivating mutations in the gene encoding MCT8 are associated with a severe form of psychomotor retardation and abnormal serum TH levels (Allan–Herndon–Dudley syndrome). In order to define the underlying pathogenic mechanisms, Mct8 knockout mice have been generated and intensively studied. Most surprisingly, Mct8 ko mice do not show any neurological symptoms but fully replicate the abnormal serum thyroid state.We will summarize the findings of these mouse studies that shed light on various aspects of Mct8 deficiency and unambiguously demonstrated the pivotal role of Mct8 in mediating TH transport in various tissues. These studies have also revealed the presence of the complex interplay between different pathogenic mechanisms that contribute to the generation of the abnormal TH serum profile.Most importantly, studies of Mct8 ko mice indicated the presence of additional TH transporters that act in concert with Mct8. Interesting candidates for such a function are the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting polypeptide Oatp1c1.Overall, the analysis of Mct8 deficient mice has greatly expanded our knowledge about the (patho-) physiological function of this transporter and established a sound basis for the characterization of additional TH transporter candidates. This article is part of a Special Issue entitled Thyroid hormone signalling.► Transporters are mandatory for proper thyroid hormone (TH) metabolism and action. ► MCT8 represents a highly specific TH transporter. ► Mutations in MCT8 are linked to neurological symptoms and abnormal TH profile. ► We review the consequences of Mct8 deficiency in mice. ► We report on the role of other TH transporters such as Oatp1c1 in mice.
Keywords: Allan–Herndon–Dudley syndrome; Monocarboxylate transporter 8; Slc16a2; L-type amino acid transporter 2; Organic anion transporting polypeptide 1c1;

Mechanisms of action of thyroid hormones in the skeleton by Anna Wojcicka; J.H. Duncan Bassett; Graham R. Williams (3979-3986).
Thyroid hormones regulate skeletal development, acquisition of peak bone mass and adult bone maintenance. Abnormal thyroid status during childhood disrupts bone maturation and linear growth, while in adulthood it results in altered bone remodeling and an increased risk of fractureThis review considers the cellular effects and molecular mechanisms of thyroid hormone action in the skeleton. Human clinical and population data are discussed in relation to the skeletal phenotypes of a series of genetically modified mouse models of disrupted thyroid hormone signaling.Euthyroid status is essential for normal bone development and maintenance. Major thyroid hormone actions in skeletal cells are mediated by thyroid hormone receptor α (TRα) and result in anabolic responses during growth and development but catabolic effects in adulthood. These homeostatic responses to thyroid hormone are locally regulated in individual skeletal cell types by the relative activities of the type 2 and 3 iodothyronine deiodinases, which control the supply of the active thyroid hormone 3,5,3’-L-triiodothyronine (T3) to its receptor.Population studies indicate that both thyroid hormone deficiency and excess are associated with an increased risk of fracture. Understanding the cellular and molecular basis of T3 action in skeletal cells will lead to the identification of new targets to regulate bone turnover and mineralization in the prevention and treatment of osteoporosis. This article is part of a Special Issue entitled Thyroid hormone signaling.► Thyroid hormones regulate bone development, peak bone mass and adult bone turnover. ► Thyroid hormone deficiency and excess are associated with increased fracture risk. ► Euthyroid status is essential for normal bone development and maintenance. ► TRα mediates the major actions of T3 in the skeleton. ► T3 exerts anabolic effects during growth but catabolic action in the adult skeleton.
Keywords: Thyroid hormone; Thyroid hormone receptor; Deiodinase; Endochondral ossification; Bone turnover; Osteoporosis;

The syndromes of reduced sensitivity to thyroid hormone by Alexandra M. Dumitrescu; Samuel Refetoff (3987-4003).
Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified.The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45 years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor β gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases.Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH.Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling.► Defects of TH action manifest as tissue and cell specific TH deficiency and excess. ► The syndrome of resistance to TH has helped elucidate the mechanism of TH action. ► Neurological deficits of MCT8 defects are more severe than in congenital hypothyroidism. ► SBP2 defects reduce selenoprotein synthesis and alter intracellular TH metabolism.
Keywords: Nuclear receptor; Selenoprotein; Deiodinase; Monocarboxylate transporter 8; Resistance to thyroid hormone; SECIS‐binding protein 2;

Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha by Nadia Schoenmakers; Carla Moran; Robin P. Peeters; Theo Visser; Mark Gurnell; Krishna Chatterjee (4004-4008).
Thyroid hormone acts via receptor subtypes (TRα1, TRβ1, TRβ2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic–pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels.This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner.Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary–thyroid axis.Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases.This article is part of a Special Issue entitled Thyroid hormone signalling.
Keywords: Resistance to thyroid hormone; Thyroid hormone receptor alpha; Dominant negative; Skeletal dysplasia;