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General and Comparative Endocrinology 152 (2007) 176–177

Discussion

Comparative thyroid endocrinology

Samantha Richardson a, Deborah Power b, Peter Klaren c

a Laboratoire de Physiologie Generale et Comparee, Museum National d’Histoire Naturelle, 7 rue Cuvier, 75231 Paris Cedex 05, Franceb CCMAR, Universidade do Algrave, Campus de Gambelas, 8000 Faro, Portugal

c Department of Animal Physiology, Faculty of Science, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands

It has been some time since comparative thyroidologistscould meet in a dedicated symposium at a Conference ofEuropean Comparative Endocrinologists.

Compared to peptide and steroid hormones, the biolog-ical activity of iodothyronines is determined by an increas-ing number of components and processes. Distributorproteins, transporters, deiodinases, conjugation and decon-jugation pathways, receptors, and promoters all determinecellular and tissue specific responses to thyroid hormones.The two State-of-the-Art lectures which opened the sympo-sium were ‘‘Novel developmental and cellular targets of thy-

roid hormone’’ (Barbara Demeneix) and ‘‘Thyroid hormone

transporters’’ (Theo Visser). These had common themesreviewing new developments in the complexities of thyroidhormone signaling pathways.

Demeneix described components of the thyroid hor-mone signaling system located downstream from the trans-membrane transport step, viz. deiodinases, thyroidhormone receptors (TRs) and their RXR dimerizationpartners and co-repressor and co-activator complexes.Early and adult neurogenesis, and the use of neural stemcells as a model system were the focus. The concept thatwithin the neural stem cell population there are niches withdifferent responsivenesses to thyroid hormone. The reactiv-ity to thyroid hormone within each niche is controlled bythe cell-specific and dynamic expression of components ofthe thyroid hormone signaling pathway. Gudernatsch’observations almost a century ago (1912) first demon-strated the involvement of thyroid hormones in amphibianmetamorphosis. Today, the response to thyroid hormonesduring the early stages of Xenopus laevis development isknown to depend upon the differential expression of deio-dinases and TRab and the presence of the ligand, T3, dur-ing this period. Later in the session, Chaminda Walpita

showed, using a prehatch zebrafish model system, thatTRab and deiodinases type-1 and -2 are expressed dynam-ically and differentially from 12 h post-fertilization

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onwards. These observations highlighted the importanceof studying other components of the thyroid hormone sig-naling pathways in addition to variations in thyroid hor-mone levels during embryonic development.

Visser moved ‘‘upstream’’ from the events involvingdeiodination and receptor expression, presenting data onthyroid hormone transmembrane transport. Specific iso-forms from several transporter families are involved inthe transfer of thyroid hormones across the blood–brainbarrier and hormone entry into brain neurons. Recently,the monocarboxylate transporter type-8 (MCT8, a memberof the T-type amino acid transporter family) has beenshown to be a specific T3 transporter (Friesema et al.,2003). The critical role of this transporter in brain develop-ment and function is dramatically illustrated by the clinicalphenotype of patients with mutations in the mct8 gene.Afflicted patients, all young boys, suffer from severe mentalretardation and a virtually complete loss of motor control.MCT8 increases the intracellular availability of T3, and,consequently, its intracellular metabolism.

Conclusion: there are many components that criticallydetermine thyroid hormone signaling, and all may be tar-gets for endocrine disruption.

The symposium addressed all vertebrate groups, and thedifferent iodothyronine molecular species. The mammalianthyroid system is well characterized, but should only beused as a first ‘‘rough’’ guide to explore the thyroid systemin other vertebrates. The symposium offered presentationsthat, quite naturally, moved from the hypothalamo–pitui-tary–thyroid axis into the periphery. In many vertebratespecies, CRH (and not TRH) is a potent thyrotropic factorfrom the hypothalamus, and chicken is no exception. Bert

De Groef extended his work on CRH as a TSH-releasingfactor (De Groef et al., 2006) by showing that somatostatininhibits the CRH-stimulated TSH release from the chickenpituitary gland. This inhibition is mediated by a somato-statin receptor type-5, the expression of which increases

S. Richardson et al. / General and Comparative Endocrinology 152 (2007) 176–177 177

towards hatching, and which again correlates with sys-temic T3 levels in the chick. The study corroborates therole of CRH as a thyrotropic factor in a number of verte-brate species, and clearly warrants further studies intohow, through the use of shared signaling molecules, thethyroid and adrenal axes are integrated. Sylvia Grommendemonstrated the presence of the TSH receptor (TSH-R)in peripheral tissues of chicken, suggesting functions ofTSH other than the control of thyroid gland function.Remarkably, the expression of TSH-R in the chicken ret-ina coincides well with that reported recently for thyro-stimulin subunits in rat eye (Nagasaki et al., 2006),suggesting a role of TSH-R outside the thyroid axis. Oris, perhaps, peripheral TSH-R truly associated with thy-roid gland tissue? Edwin Geven discussed heterotopic func-tional thyroid tissue in common carp (Cyprinus carpio),and showed it is the kidney (and not the subpharyngealarea) that accumulates iodide, produces thyroid hor-mones, and releases T4 in vitro upon stimulation withTSH. Should we recheck our histology for heterotopicthyroid follicles, or is TSH a pleiotropic hormone and isthe search now on for multiple functions?

In terrestrial and freshwater habitats, iodine and sele-nium (the essential ingredient of the deiodinase selenopro-tein) are present in trace amounts. This makes thyroidhormone action dependent on two trace elements, and itcan be envisaged that there would be evolutionary pres-sure favouring the exploitation of all iodine atoms in theiodothyronine molecule. Removing one iodine from thy-roxine yields the potently bioactive 3,5,3 0-triiodothyronine(T3), and this illustrates the impact of one iodine atom onthe biological activity of a molecule. The iodine atoms inT3 can be successively removed to yield di- and monoiod-othyronines with different steric properties and (thus) dif-ferent biological activities. Other pathways includedeamination, decarboxylation, and conjugation. Theassignment of a biological activity to the iodothyroninemetabolites originating from these would be a way to ‘‘eco-nomically’’ fully exploit trace elements. The work of Fer-nando Goglia and his co-workers on the effects ofdiiodothyronines on mitochondrial physiology is of especialinterest (Goglia, 2005), and we should be prepared for sur-prising biological effects of ‘‘unsuspected’’ iodothyroninemetabolites, as demonstrated recently by Scanlan et al.(2004) for the deiodinated decarboxylated thyroid hormonemetabolite 3-T1AM. New experimental data on 3,5-diiodo-thyronine in fish and the glucuronidated conjugates of T4and T3 in rat obtained by, respectively, Aurea Orozco andSabine van der Heide (2006, communicated by Peter Klaren)added further evidence to the concept that iodothyroninesother than T3 (and T4) are biologically active signalingmolecules.

It was long thought that, apart from albumin and lipo-proteins, fishes went without specific plasma thyroid hor-mone distributor proteins. Recently, teleosteantransthyretin (TTR) was first identified in gilthead sea-bream (Sparus auratus) by Deborah Power and colleagues(Santos and Power, 1999), and this makes teleost TTRthe common ancestor of the tetrapod orthologues. It wassoon found that fish TTR has a different affinity for T4and T3, and that, despite a relatively low sequence identity,the thyroid hormone binding domain in Sparus TTR is wellconserved. Preliminary studies in seabream indicate thatthyroid hormones may regulate TTR production. Lidia

Mayorga and Patricia Villalobos presented the first primarystructures and biochemical properties of deiodinase type-3of an elasmobranch (Chiloscyllium punctatum, brown-banded bambooshark) and a reptile (Pituophis deppei,Mexican pine snake). This is a first and important step toextend knowledge of the peripheral thyroid hormonemetabolism in two classes of vertebrates that, to date, havebeen largely ignored in this respect.

The symposium showed one of comparative endocrinol-ogy’s raisons d’etre: non-mammalian vertebrates provideexcellent model systems for the study of integrated regula-tory systems, and are a virtually infinite pool of model sys-tems to study thyroid hormone functions and mechanisms.

References

De Groef, B., Van der Geyten, S., Darras, V.M., Kuhn, E.R., 2006. Roleof corticotropin-releasing hormone as a thyrotropin-releasing factor innon-mammalian vertebrates. Gen. Comp. Endocrinol. 146, 62–68.

Friesema, E.C.H., Ganguly, S., Abdalla, A., Manning Fox, J.E., Hale-strap, A.P., Visser, T.J., 2003. Identification of monocarboxylatetransporter 8 as a specific thyroid hormone transporter. J. Biol. Chem.278, 40128–40135.

Goglia, F., 2005. Biological effects of 3,5-diiodothyronine (T2). Biochem-istry (Mosc.) 70, 164–172.

Gudernatsch, J.F., 1912. Feeding experiments on tadpoles: I. Theinfluence of specific organs given as food on growth and differentia-tion. A contribution to the knowledge of organs of internal secretion.Roux’ Arch. Dev. Biol. 35, 457–483.

Nagasaki, H., Wang, Z., Jackson, V.R., Lin, S., Nothacker, H.-P., Civelli,O., 2006. Differential expression of the thyrostimulin subunits, glyco-protein a2 and b5 in the rat pituitary. J. Mol. Endocrinol. 37, 39–50.

Santos, C.R., Power, D.M., 1999. Identification of transthyretin in fish(Sparus aurata): cDNA cloning and characterisation. Endocrinology140, 2430–2433.

Scanlan, T.S., Suchland, K.L., Hart, M.E., Chiellini, G., Huang, Y.,Kruzich, P.J., Frascarelli, S., Crossley, D.A., Bunzow, J.R., Ronca-Testoni, S., Lin, E.T., Hatton, D., Zucchi, R., Grandy, D.K., 2004. 3-Iodothyronamine is an endogenous and rapid-acting derivative ofthyroid hormone. Nature Med. 10, 638–642.

van der Heide, S.M., Joosten, B.J.L.J., Dragt, B.S., Everts, M.E., Klaren,P.H.M., 2006. A physiological role for glucuronidated thyroidhormones: preferential uptake by H9c2(2-1) myotubes. Mol. Cell.Endocrinol., doi:10.1016/j.mce.2006.1010.1012.