Thyroid Hormone Receptors and Action

Séminaire FSER organisé par Ana Aranda (Instituto de Investigaciones Biomédicas “Alberto Sols”, Madrid) et Herb Samuels (LaGuardia Community College/CUNY, Long Island City) du 28 février au 5 mars 2011

Participants

Ana Aranda, Krishna V. Chatterjee, Sheue-Uann Cheng, Amedeo Columbano, Barbara Demeinex, Wolfgang H. Dillmann, Jean-Baptiste Fini, Frédéric Flamant, Douglas Forrest, Miguel Lopez, Jens Mittag, Michela Plateroti, Martin L. Privalsky, Laurent Sachs, Herb Samuels, Yun-Bo Shi, Maria Sirakov, Björn Vennström, Graham Williams, Alberto Zambrano

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Compte-rendu

The mists rose each morning from the vineyards, light winds filtered through the olive tree groves, and discussions of thyroid hormone function filled the air at the 2011 Thyroid Hormone Receptors and Action meeting, hosted by the Fondation des Treilles in Provence, France. From February 28 to March 4, nineteen scientists shared their latest insights on how thyroid hormone contributes to normal biology, and how abnormalities in thyroid hormone signaling result in disease.

The conference began on Day 1 of the scientific sessions with a wide-ranging discussion of the mechanisms of thyroid hormone receptor action in health and in disease. Douglas Forrest opened the morning session by describing the role of thyroid hormone and thyroid hormone receptor (TR)-b2, in the development of color vision. Dr. Forrest detailed how the proper levels of thyroid hormone promote the formation of the M cone cells that specialize in green light sensing by the retina, whereas excess thyroid hormone leads to cone cell depletion. Barbara Demeneix described the roles of specific TR isoforms in the thyroid-hormone driven repression of genes in the brain, and revealed new studies that define a role for TRa1 in the regulation of adult neural stem cell proliferation and identity. Turning the discussion from normal to aberrant TR function, Krishna Chatterjee next described several newly discovered metabolic phenotypes associated with human Resistance to Thyroid Hormone Syndrome, including enhanced mitochondrial uncoupling and hyperphagia; Dr. Chatterjee also presented data on the parallel universe of peroxisome-proliferator activated receptor (PPAR)-g, a cousin receptor to the TRs that, when mutated in humans, can result in insulin resistance, partial lipodystrophy, hepatic steatosis, and acanthosis nigricans. Initiating the afternoon session, Graham Williams discussed the intricacies of investigating the cell lineage-specific effects of thyroid hormone signaling through the targeted overexpression of the inactivating deodinase (DIO 3). This was followed by Wolfgang Dillmann’s description of the many actions of thyroid hormone and its receptors in control of the cardiovascular system. The contributions of specific TR isoforms in the regulation of diastolic relaxation and in fuel flux in the heart were described, as were the effects of hypo- and hyperthyroidism in cardiac hypertrophy, vascularization, and in protection from ischemic damage. Yun-Bo Shi next presented his wide-ranging work investigating the actions of thyroid hormone in amphibian development, focusing on the contributions of the different TR isoforms, and their coregulatory proteins, to the timing and tissue specificity of metamorphosis. The day was completed by Laurent Sachs, who applied an impressive panel of high-throughput sequence methodologies to a dissection of the roles of thyroid hormone in Xenopus development. Using these approaches, Dr. Sachs was able to identify the Xenopus genes that respond to thyroid hormone during metamorphosis, the TR binding sites on the DNA that mediate these responses, the associated changes in chromatin modifications, and the long range interactions between different TR binding sites in the genome that operate together to yield the appropriate patterns of gene regulation.

Day 2 began with a darker hue by focusing on the actions of thyroid hormone and its receptors in cancer. Sheue-yann Cheng explained how a strong, dominant-negative mutant of TRb1, first discovered as a causal agent in human Thyroid Hormone Resistance Syndrome, helps mediate thyroid neoplasia in mice through physical interaction with, and enhancement of, a series of pro-proliferative and pro-survival signaling pathways that operate downstream of the c-Src kinase. Dr. Cheng also detailed how wild-type TRb1, conversely, suppresses tumorigenesis by inhibiting many of these same pathways. Martin Privalsky next described how TR mutants found in hepatocellular and renal clear cell carcinomas display alterations in their target gene and corepressor specificities that may contribute to neoplastic progression in these tumors. Ana Aranda revealed how a corepressor-dependent inhibition of c-Ras action, inhibition of MAP kinase and PI3 kinase pathways, and repression of a series of pro-metastatic genes helps mediate the tumor-suppressor properties of wild-type TRb1. Dr. Aranda also determined that TRs have intriguingly mixed effects in a skin cancer model: a double knockout of both TRa and TRb loci reduced the incidence of tumors, but enhanced their progression and produced a switch from papillomas to squamous cell carcinomas. A similar dualism was reported by Amedeo Columbano in his studies of the effects of thyroid hormone on hepatocarcinomas; Dr. Columbano presented results showing that thyroid hormone or TRb-specific ligands were strongly promitogenic for normal liver hepatocytes, yet reduced the number of pre-neoplastic lesions in a diethylnitrosamine-model of liver cancer. This reduction in preneoplastic lesions was associated with a loss of fetal markers and reacquisition of normal hepatocyte markers, suggesting that TRs mediates both pro-replicative and pro-differentiation signals. Alberto Zambrano rounded out the discussion by demonstrating that thyroid hormone can promote cellular senescence; this function was specific to TRb1 and appeared to be mediated through an increase in double-stranded DNA breaks and ATR/ATM activation, most likely through an increase in reactive-oxygen species. Finally, Graham Williams completed the evening session by returning to a discussion of thyroid hormone action on bone. Through clever use of targeted DIO3 expression as a means to selectively reduce thyroid hormone levels in specific cell lineages, Williams was able to demonstrate a key role for thyroid hormone in skeletal formation by chondrocytes and osteoblasts.

Day 3 began with a focus on thyroid hormone signaling in the intestine. Michela Plateroti explained how T3, operating primarily through TRa1, promotes maturation of the mammalian intestine, regulates proliferation of the cells in the intestinal crypt, and contributes to epithelial regeneration after irradiation through effects on an adult stem cell population; gene expression analysis implicated components of the Wnt signaling pathway in at least several of these processes. Highlighting the truth of the old adage that too much of a good thing can be bad, Dr. Plateroti also showed that targeted overexpression of TRa1 produced an expanded crypt progenitor population, resulting in increased incidence of spontaneous adenomas; crossing these mice with a APC-mutant strain resulted in accelerated adenocarcinoma formation and metastasis. Yun-Bo Shi extended the gut level discussion to the Xenopus amphibian model. By careful dissection and reconstitution of Xenopus gut epithelium and adjacent « non-epithelial » tissue from genetically manipulated Xenopus, Dr. Shi demonstrated that TR signaling was required in both layers to produce the correct repertoire of stem cells and differentiated epithelium found in the adult gut. Finishing the session, Maria Sirakov presented evidence that TRa1 can affect Wnt signaling in the mammalian intestinal epithelium, at least in part, by a physical interaction with the b-catenin/Tcf4 complex, and that b-catenin/Tcf4 reciprocally interferes with transcriptional activation by TRa1.

Friday morning was devoted to discussions of the actions of thyroid hormone in the brain. Miguel López began the session with descriptions of the complex regulatory network within the hypothalamus that controls feeding behavior and energy balance in mammals, and described the actions of thyroid hormone on the AMPK and malonyl CoA signaling pathways that are key mediators within this network. Frédéric Flamand described his elegant use of targeted genetic manipulations to determine the contributions of thyroid hormone signaling to the differentiation, proliferation, migration, connectivity, and survival of specific cell lineages within the developing cerebellum. Douglas Forrest then took to the stage to detail the cis-regulatory sequences and trans-acting factors that define the cell-type specific expression of the TRb2 isoform in retinal cone cells, in cochlear sensory hair cells, and in the pituitary. Jean-Baptiste Fini next discussed the interplay between T3, T4, deiodinases, and the different TR isoforms in amphibian neuronal differentiation, and the effects of endocrine disruptors, such as TBBPA, on these pathways. Björn Vennström followed with an comprehensive and illuminating description of the effects of a TRa1 mutation on a series of developmental, metabolic, endocrine, and neurological processes in mice; these studies, taken as a whole, revealed an extraordinarily wide ranging role of TRa1 in mammalian biology. Jens Mittag closed the final session with a highly informative description of the effects of thyroid hormone on the autonomous nervous system, focusing on a newly recognized population of thermosensitive pv+ neurons in the anterior hypothalamus that are developmentally dependent on TR function for their formation, and that help mediate the adaptation of cardiac output in response to stress, activity or temperature.

This brief summary does not capture that many wonderful, creative discussions over meals or coffee, or the casual exchange of ideas during walks around the beautiful conference grounds. The participants departed on the final day deeply appreciative to the Fondation des Treilles for the opportunity to share their latest experimental results, theories, and insights. Everyone also expressed the sincere hope that this meeting would become the prototype for a series of future thyroid hormone conferences at the same lovely and intellectually-stimulating location.