Thyroid Hormone Receptors in Two Model Species for Vertebrate Embryonic Development: Chicken and Zebrafish

Chicken and zebrafish are two model species regularly used to study the role of thyroid hormones in vertebrate development. Similar to mammals, chickens have one thyroid hormone receptor α (TRα) and one TRβ gene, giving rise to three TR isoforms: TRα, TRβ2, and TRβ0, the latter with a very short amino-terminal domain. Zebrafish also have one TRβ gene, providing two TRβ1 variants. The zebrafish TRα gene has been duplicated, and at least three TRα isoforms are expressed: TRαA1-2 and TRαB are very similar, while TRαA1 has a longer carboxy-terminal ligand-binding domain. All these TR isoforms appear to be functional, ligand-binding receptors. As in other vertebrates, the different chicken and zebrafish TR isoforms have a divergent spatiotemporal expression pattern, suggesting that they also have distinct functions. Several isoforms are expressed from the very first stages of embryonic development and early chicken and zebrafish embryos respond to thyroid hormone treatment with changes in gene expression. Future studies in knockdown and mutant animals should allow us to link the different TR isoforms to specific processes in embryonic development

Effects of experimentally sustained elevated testosterone on incubation behaviour and reproductive success in female great tits (Pants major)

n many seasonally breeding birds, female and male testosterone (T) levels peak at the start of the breeding season, coinciding with pair bonding and nesting activities. Shortly after the onset of egg laying, T levels slowly decline to baseline levels in both sexes, but more rapidly so in females. During this period, T in males may still function to facilitate territorial behaviour, mate guarding and extra pair copulations, either via short lasting peaks or elevated basal levels of the hormone. In some species, however, males become insensitive to increased T after the onset of egg laying. It has been postulated that in these species bi-parental care is essential for offspring survival, as T is known to inhibit paternal care. However, only very few studies have analysed this for females. As females are heavily involved in parental care, they too might become insensitive to T after egg laying. Alternatively, because territorial defence, mate guarding and extra pair copulations are expected to be less important for females than for males, they may not have had the need to evolve a mechanism to become insensitive to T during the period of maternal care, because their natural T levels are never elevated during this part of the breeding season anyway. We tested these alternative hypotheses in female great tits (Parus major). Male great tits have previously been shown to be insensitive to T after egg laying with regard to nestling feeding behaviour (but not song rate). When females had started nest building, we experimentally elevated their T levels up to the nestling feeding phase, and measured incubation behaviour (only females incubate) and reproductive success. T did not significantly affect nest building or egg laying behaviour, although egg laying tended to be delayed in T females. Females with experimentally enhanced T maintained lower temperature during incubation but did not spend less time incubating. This might explain the reduced hatching success of their eggs, smaller brood size and lower number of fledglings we found in this study. As in this species T-dependent behaviour by females during the phase of parental care is not needed, the results support the hypothesis that in this species the need for selection in favour of T-insensitivity did not occur

Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration

Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O DKO) mice. Analysis of tissue TH content and expression of TH-regulated genes indicate a thyrotoxic state in Mct8-deficient skeletal muscles. Both TH transporters are upregulated in activated satellite cells (SCs). In M/O DKO mice, we observed a strongly reduced number of differentiated SCs, suggesting an impaired stem cell function. Moreover, M/O DKO mice and mice lacking both transporters exclusively in SCs showed impaired skeletal muscle regeneration. Our data provide solid evidence for a unique gate-keeper function of MCT8 and OATP1C1 in SC activation, underscoring the importance of a finely tuned TH signaling during myogenesis. In this article, Mayerl and colleagues demonstrate that the thyroid hormone transporters MCT8 and OATP1C1 are unique gate-keepers in activated muscle stem cells. The expression of both transporters increases upon activation of muscle stem cells, while loss of MCT8 and OATP1C1 expression results in impaired muscle stem cell differentiation

Thyroid Hormone Signalling Genes Are Regulated by Photoperiod in the Hypothalamus of F344 Rats

Seasonal animals adapt their physiology and behaviour in anticipation of climate change to optimise survival of their offspring. Intra-hypothalamic thyroid hormone signalling plays an important role in seasonal responses in mammals and birds. In the F344 rat, photoperiod stimulates profound changes in food intake, body weight and reproductive status. Previous investigations of the F344 rat have suggested a role for thyroid hormone metabolism, but have only considered Dio2 expression, which was elevated in long day photoperiods. Microarray analysis was used to identify time-dependent changes in photoperiod responsive genes, which may underlie the photoperiod-dependent phenotypes of the juvenile F344 rat. The most significant changes are those related to thyroid hormone metabolism and transport. Using photoperiod manipulations and melatonin injections into long day photoperiod (LD) rats to mimic short day (SD), we show photoinduction and photosuppression gene expression profiles and melatonin responsiveness of genes by in situ hybridization; TSHβ, CGA, Dio2 and Oatp1c1 genes were all elevated in LD whilst in SD, Dio3 and MCT-8 mRNA were increased. NPY was elevated in SD whilst GALP increased in LD. The photoinduction and photosuppression profiles for GALP were compared to that of GHRH with GALP expression following GHRH temporally. We also reveal gene sets involved in photoperiodic responses, including retinoic acid and Wnt/ß-catenin signalling. This study extends our knowledge of hypothalamic regulation by photoperiod, by revealing large temporal changes in expression of thyroid hormone signalling genes following photoperiod switch. Surprisingly, large changes in hypothalamic thyroid hormone levels or TRH expression were not detected. Expression of NPY and GALP, two genes known to regulate GHRH, were also changed by photoperiod. Whether these genes could provide links between thyroid hormone signalling and the regulation of the growth axis remains to be investigated

Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNAdamaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging

Deficiency of the thyroid hormone transporter Monocarboxylate Transporter 8 in neural progenitors impairs cellular processes crucial for early corticogenesis

Thyroid hormones (THs) are essential for establishing layered brain structures, a process called corticogenesis, by acting on transcriptional activity of numerous genes. In humans, deficiency of the monocarboxylate transporter 8 (MCT8), involved in cellular uptake of THs before their action, results in severe neurological abnormalities, known as the Allan-Herndon-Dudley syndrome. While the brain lesions predominantly originate prenatally, it remains unclear how and when exactly MCT8 dysfunction affects cellular processes crucial for corticogenesis. We investigated this by inducing in vivo RNAi vector-based knockdown of MCT8 in neural progenitors of the chicken optic tectum, a layered structure that shares many developmental features with the mammalian cerebral cortex. MCT8 knockdown resulted in cellular hypoplasia and a thinner optic tectum. This could be traced back to disrupted cell-cycle kinetics and a premature shift to asymmetric cell divisions impairing progenitor cell pool expansion. Birth-dating experiments confirmed diminished neurogenesis in the MCT8-deficient cell population as well as aberrant migration of both early-born and late-born neuroblasts, which could be linked to reduced reelin signaling and disorganized radial glial cell fibers. Impaired neurogenesis resulted in a reduced number of glutamatergic and GABAergic neurons, but the latter additionally showed decreased differentiation. Moreover, an accompanying reduction in untransfected GABAergic neurons suggests hampered intercellular communication. These results indicate that MCT8-dependent TH uptake in the neural progenitors is essential for early events in corticogenesis, and help to understand the origin of the problems in cortical development and function in Allan-Herndon-Dudley syndrome patients.SIGNIFICANCE STATEMENT Thyroid hormones (THs) are essential to establish the stereotypical layered structure of the human forebrain during embryonic development. Before their action on gene expression, THs require cellular uptake, a process facilitated by the TH transporter monocarboxylate transporter 8 (MCT8). We investigated how and when dysfunctional MCT8 can induce brain lesions associated with the Allan-Herndon-Dudley syndrome, characterized by psychomotor retardation. We used the layered chicken optic tectum to model cortical development, and induced MCT8 deficiency in neural progenitors. Impaired cell proliferation, migration, and differentiation resulted in an underdeveloped optic tectum and a severe reduction in nerve cells. Our data underline the need for MCT8-dependent TH uptake in neural progenitors and stress the importance of local TH action in early development.status: publishe

Ghrelin in Birds: Its Structure, Distribution and Function

Feeding and somatic growth are closely related to each other, and are strictly governed by several endocrine and neuroendocrine systems in animals. Endocrine control of growth is an important subject in poultry industry. Ghrelin is a recently identified, growth hormone (GH)-releasing and feeding-promoting peptide in mammals, and the major source of its release is the stomach. From the comparative endocrinological aspects, ghrelin was considered to be present in avian species. In fact, ghrelin peptide and its cDNA encoding ghrelin precursor have been identified from the chicken proventriculus in 2002, and the presence of the ghrelin molecule has by now been shown in various avian species. In this review, we summarize the recent knowledge of ghrelin structure, distribution and function in birds