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- Post-embryonic remodelling of neurocranial elements: a comparative study of normal versus abnormal eye migration in a flatfish, the Atlantic halibutPublication . Saele, O; Silva, Nadia; Pittman, KThe process of eye migration in bilaterally symmetrical flatfish larvae starts with asymmetrical growth of the dorsomedial parts of the ethmoid plate together with the frontal bones, structures initially found in a symmetrical position between the eyes. The movement of these structures in the future ocular direction exerts a stretch on the fibroblasts in the connective tissue found between the moving structures and the eye that is to migrate. Secondarily, a dense cell population of fibroblasts ventral to the eye starts to proliferate, possibly cued by the pulling forces exerted by the eye. The increased growth ventral to the eye pushes the eye dorsally. Osteoblasts are deposited in the dense cell layer, forming the dermal part of the lateral ethmoid, and at full eye migration this will cover the area vacated by the migrated eye. When the migrating eye catches up with the previous migrated dermal bones, the frontals, these bones will be remodelled to accommodate the eye. Our findings suggest that a combination of extremely localized signals and more distant factors may impinge upon the outcome of the tissue remodelling. Early normal asymmetry of signalling factors may cascade on a series of events.
- Molecular and cellular changes in skin and muscle during metamorphosis of Atlantic halibut (Hippoglossus hippoglossus) are accompanied by changes in deiodinases expressionPublication . Campinho, Marco António; Galay-Burgos, M.; Silva, Nádia; Costa, R. A.; Alves, Ricardo N.; Sweeney, Glen E.; Power, DeborahFlatfish metamorphosis is the most dramatic postnatal developmental event in teleosts. Thyroid hormones (TH), thyroxine (T4) and 3,3′-5′-triiodothyronine (T3) are the necessary and sufficient factors that induce and regulate flatfish metamorphosis. Most of the cellular and molecular action of TH is directed through the binding of T3 to thyroid nuclear receptors bound to promoters with consequent changes in the expression of target genes. The conversion of T4 to T3 and nuclear availability of T3 depends on the expression and activity of a family of 3 selenocysteine deiodinases that activate T4 into T3 or degrade T4 and T3.
- A thyroid hormone regulated asymmetric responsive centre is correlated with eye migration during flatfish metamorphosisPublication . Campinho, Marco António; Silva, Nádia; Martins, Gabriel G.; Anjos, Liliana; Florindo, Claudia; Roman-Padilla, Javier; Garcia-Cegarra, Ana; Louro, Bruno; Manchado, Manuel; Power, DeborahFlatfish metamorphosis is a unique post-embryonic developmental event in which thyroid hormones (THs) drive the development of symmetric pelagic larva into asymmetric benthic juveniles. One of the eyes migrates to join the other eye on the opposite side of the head. Developmental mechanisms at the basis of the acquisition of flatfish anatomical asymmetry remain an open question. Here we demonstrate that an TH responsive asymmetric centre, determined by deiodinase 2 expression, ventrally juxtaposed to the migrating eye in sole (Solea senegalensis) correlates with asymmetric cranial ossification that in turn drives eye migration. Besides skin pigmentation that is asymmetric between dorsal and ventral sides, only the most anterior head region delimited by the eyes becomes asymmetric whereas the remainder of the head and organs therein stay symmetric. Sub-ocular ossification is common to all flatfish analysed to date, so we propose that this newly discovered mechanism is universal and is associated with eye migration in all flatfish.
- The molecular and endocrine basis of flatfish metamorphosisPublication . Power, Deborah; Einarsdóttir, Ingibjörg E.; Pittman, Karin; Sweeney, Glen E.; Hildahl, Jon; Campinho, Marco António; Silva, Nadia; Saele, Oystein; Galay-Burgos, M.; Smaàradóttir, Heiddis; Björnsson, Björn ThrandurA significant component of aquaculture is the production of good quality larvae, and, in the case of flatfish, this is tied up with the change from a symmetric larva to an asymmetric juvenile. Despite the pioneering work carried out on the metamorphosis of the Japanese flounder (Paralichthys olivaceus) and summer flounder (Paralichthys dentatus), the underlying molecular basis of flatfish metamorphosis is still relatively poorly characterized. It is a thyroid hormone (TH) driven process, and the role of other hormones in the regulation of the process along with the interplay of abiotic factors are still relatively poorly characterized as is the extent of tissue and organ remodeling, which underlie the profound structural and functional modifications that accompany the larval/juvenile transition. The isolation of genes for hormones, receptors, binding proteins, and other accessory factors has provided powerful tools with which to pursue this question. The application of molecular methodologies such as candidate gene approaches and microarray analysis coupled to functional genomics has started to contribute to understanding the complexity of tissue and organ modifications that accompany flatfish metamorphosis. A better understanding of the biology of normal metamorphosis is essential to identify factors contributing to abnormal metamorphosis.
- In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversityPublication . Silva, Nadia; Campinho, Marco AntónioMaternally derived thyroid hormone (T3) is a fundamental factor for vertebrate neurodevelopment. In humans, mutations on the thyroid hormones (TH) exclusive transporter monocarboxylic acid transporter 8 (MCT8) lead to the Allan-Herndon-Dudley syndrome (AHDS). Patients with AHDS present severe underdevelopment of the central nervous system, with profound cognitive and locomotor consequences. Functional impairment of zebrafish T3 exclusive membrane transporter Mct8 phenocopies many symptoms observed in patients with AHDS, thus providing an outstanding animal model to study this human condition. In addition, it was previously shown in the zebrafish mct8 KD model that maternal T3 (MTH) acts as an integrator of different key developmental pathways during zebrafish development. MethodsUsing a zebrafish Mct8 knockdown model, with consequent inhibition of maternal thyroid hormones (MTH) uptake to the target cells, we analyzed genes modulated by MTH by qPCR in a temporal series from the start of segmentation through hatching. Survival (TUNEL) and proliferation (PH3) of neural progenitor cells (dla, her2) were determined, and the cellular distribution of neural MTH-target genes in the spinal cord during development was characterized. In addition, in-vivo live imaging was performed to access NOTCH overexpression action on cell division in this AHDS model. We determined the developmental time window when MTH is required for appropriate CNS development in the zebrafish; MTH is not involved in neuroectoderm specification but is fundamental in the early stages of neurogenesis by promoting the maintenance of specific neural progenitor populations. MTH signaling is required for developing different neural cell types and maintaining spinal cord cytoarchitecture, and modulation of NOTCH signaling in a non-autonomous cell manner is involved in this process. DiscussionThe findings show that MTH allows the enrichment of neural progenitor pools, regulating the cell diversity output observed by the end of embryogenesis and that Mct8 impairment restricts CNS development. This work contributes to the understanding of the cellular mechanisms underlying human AHDS.
- The goitrogenic efficiency of thioamides in a marine teleost, sea bream (Sparus auratus)Publication . Campinho, Marco António; Morgado, Isabel; Pinto, Patricia IS; Silva, Nádia; Power, DeborahStudies on the role of thyroid hormones (THs) in teleost fish physiology have deployed the synthetic goitrogens, methimazol (MMI), propilthiouracil (PTU) and thiourea (TU) that are used to treat human hyperthyroidism. However, the action of the goitrogens, MMI, PTU and TU at different levels of the hypothalamic–pituitary–thyroid (HPT) axis in teleosts is largely unknown. The central importance of the hypothalamus and pituitary in a number of endocrine regulated systems and the cross-talk that occurs between different endocrine axes makes it pertinent to characterize the effects of MMI, PTU and TU, on several endpoints of the thyroid system. The marine teleost, sea bream (Sparus auratus) was exposed to MMI, PTU and TU (1 mg/kg wet weight per day), via the diet for 21 days. Radioimmunoassays (RIA) of plasma THs and ELISA of the TH carrier transthyretin (TTR) revealed that MMI was the only chemical that significantly reduced plasma TH levels (p < 0.05), although both MMI and PTU significantly (p < 0.05) reduced plasma levels of circulating TTR (p < 0.05). Histological analysis of the thyroid tissue revealed modifications in thyrocyte activity that explain the reduced circulating levels of THs. MMI also significantly (p < 0.05) up-regulated transcript abundance of liver deiodinase 1 and 2 while significantly (p < 0.05) decreasing TRb expression in the pituitary, all hallmarks of HPT axis action of goitrogens in vertebrates. The results indicate that in the sea bream MMI is the most effective goitrogen followed by PTU and that TU (1 mg/kg wet weight for 21 days) failed to have a goitrogenic effect. The study highlights the non-uniform effect of goitrogens on the thyroid axis of sea bream and provides the basis for future studies of thyroid disrupting pollutants.
- Regulation of calcium balance in the sturgeon Acipenser naccarii: a role for PTHrPPublication . Fuentes, J.; Haond, Christophe; Guerreiro, P. M.; Silva, Nádia; Power, Deborah; Canario, Adelino V. M.Calcium regulation in sturgeon is of special interest because they are a representative of the ancient fishes possessing mainly cartilaginous skeletons and a supposedly low calcium demand. The present study aimed to characterize the effect of a chronic absence of dietary calcium and the effect of parathyroid hormone-related protein (PTHrPA) (1-34) (7) on calcium balance in juvenile sturgeon (Acipenser naccarii). At rest, sturgeon juveniles are in net positive calcium balance, since whole body calcium uptake is significantly higher than efflux and calcium accumulates in the body. To study the importance of dietary calcium, the sturgeon were kept on a calcium-free diet for 8 wk. This manipulation impaired growth as measured by failure to gain weight or increase in length and indicates that dietary calcium is important for growth in sturgeon. An increased whole body calcium uptake partially compensated dietary calcium deficiency and was associated with increased gill chloride cell number in lamellae and filaments in parallel with increased gill Na(+)K(+)-ATPase activity. In addition, a single injection of piscine PTHrP(1-34) significantly increased whole body calcium uptake and decreased whole body calcium efflux. Administration of PTHrP significantly increased circulating plasma calcium 4-24 h postinjection. The increase in net calcium transport and increased plasma levels of calcium is consistent with the actions of a hypercalcemic factor. It would appear that the sturgeon rely on calcium for growth and tightly regulate calcium transport. The action in calcium balance is consistent with PTHrP acting as a hypercalcemic factor in sturgeon.
- Expression of the myosin light chains 1 and 2 in the developing fast muscle of gilthead sea bream (Sparus aurata)Publication . Moutou, Katerina A.; Silva, Nadia; Mamuris, Z.; Power, DeborahMyosin, the major component of striated muscle, is a complex molecule of heavy and light chains, which undergo continuous replacement to meet developmental and environmental demands. A range of myosin isoforms are expressed in early developmental stages and are of special interest as they offer information about muscle formation and function early in life. In addition, they can act as markers for the study of prenatal events with an effect on postnatal growth performance. In this study, the spatial and temporal expression of embryonic myosin light chains 1 (MLC1) and 2 (MLC2) was studied in sea bream larvae post-hatch by in situ hybridization using riboprobes.
- Troponin T isoform expression is modulated during Atlantic Halibut metamorphosisPublication . Campinho, M. A.; Silva, Nadia; Nowell, Mari; Llewellyn, Lynda; Sweeney, Glen E.; Power, DeborahBackground: Flatfish metamorphosis is a thyroid hormone (TH) driven process which leads to a dramatic change from a symmetrical larva to an asymmetrical juvenile. The effect of THs on muscle and in particular muscle sarcomer protein genes is largely unexplored in fish. The change in Troponin T (TnT), a pivotal protein in the assembly of skeletal muscles sarcomeres and a modulator of calcium driven muscle contraction, during flatfish metamophosis is studied. Results: In the present study five cDNAs for halibut TnT genes were cloned; three were splice variants arising from a single fast TnT (fTnT) gene; a fourth encoded a novel teleost specific fTnTlike cDNA (AfTnT) expressed exclusively in slow muscle and the fifth encoded the teleost specific sTnT2. THs modified the expression of halibut fTnT isoforms which changed from predominantly basic to acidic isoforms during natural and T4 induced metamorphosis. In contrast, expression of red muscle specific genes, AfTnT and sTnT2, did not change during natural metamorphosis or after T4 treatment. Prior to and after metamorphosis no change in the dorso-ventral symmetry or temporal-spatial expression pattern of TnT genes and muscle fibre organization occurred in halibut musculature. Conclusion: Muscle organisation in halibut remains symmetrical even after metamorphosis suggesting TH driven changes are associated with molecular adaptations. We hypothesize that species specific differences in TnT gene expression in teleosts underlies different larval muscle developmental programs which better adapts them to the specific ecological constraints.
- Measuring healthy ageing: current and future toolsPublication . Silva, Nádia; Rajado, Ana Teresa; Esteves, Filipa; Brito, David V.C.; Apolónio, Joana; Roberto, Vânia; Binnie, Alexandra; Araújo, Inês Maria; Nóbrega, Clévio; Bragança, José; Castelo-Branco, PedroHuman ageing is a complex, multifactorial process characterised by physiological damage, increased risk of age-related diseases and inevitable functional deterioration. As the population of the world grows older, placing significant strain on social and healthcare resources, there is a growing need to identify reliable and easy-to-employ markers of healthy ageing for early detection of ageing trajectories and disease risk. Such markers would allow for the targeted implementation of strategies or treatments that can lessen suffering, disability, and dependence in old age. In this review, we summarise the healthy ageing scores reported in the literature, with a focus on the past 5 years, and compare and contrast the variables employed. The use of approaches to determine biological age, molecular biomarkers, ageing trajectories, and multi-omics ageing scores are reviewed. We conclude that the ideal healthy ageing score is multisystemic and able to encompass all of the potential alterations associated with ageing. It should also be longitudinal and able to accurately predict ageing complications at an early stage in order to maximize the chances of successful early intervention.
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