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Anatomical Assessment of the Adult Skeleton of Zebrafish Reared Under Different Thyroid Hormone Profiles.

ABSTRACT: Thyroid hormone (TH) directs the growth and maintenance of tissues throughout the body during development and into adulthood, and plays a particularly important role in proper ossification and homeostasis of the skeleton. To better understand the roles of TH in the skeletogenesis of a vertebrate model, and to define areas of the skeleton that are particularly sensitive to developmental TH, we examined the effects of hypo- and hyperthyroidism on skeletal development in zebrafish. Performing a bone-by-bone anatomical assessment on the entire skeleton of adult fish, we found that TH is required for proper ossification, growth, morphogenesis, and fusion of numerous bones. We showed that the pectoral girdle, dermatocranium, Weberian apparatus, and dentary are particularly sensitive to TH, and that TH affects development of skeletal element regardless of bone type and developmental origin. Indeed, the hormone does not universally promote ossification: we found that developmental TH prevents ectopic ossification in multiple thin bones and within connective tissue of the jaw. In all, we found that TH regulates proper morphogenesis and ossification in the majority of zebrafish bones, and that the requirement for the hormone extends across bone types and developmental profiles. Anat Rec, 302:1754-1769, 2019. © 2019 American Association for Anatomy.

SUBMITTER: Keer S

PROVIDER: S-EPMC6800157 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Anatomical Assessment of the Adult Skeleton of Zebrafish Reared Under Different Thyroid Hormone Profiles.

Keer Stephanie S Cohen Karly K May Catherine C Hu Yinan Y McMenamin Sarah S Hernandez Luz Patricia LP

Anatomical record (Hoboken, N.J. : 2007) 20190429 10

Thyroid hormone (TH) directs the growth and maintenance of tissues throughout the body during development and into adulthood, and plays a particularly important role in proper ossification and homeostasis of the skeleton. To better understand the roles of TH in the skeletogenesis of a vertebrate model, and to define areas of the skeleton that are particularly sensitive to developmental TH, we examined the effects of hypo- and hyperthyroidism on skeletal development in zebrafish. Performing a bon ...[more]

PMID: 30989809

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Project description:Background: Mutations of thyroid hormone receptor α1 (TRα1) cause resistance to thyroid hormone (RTHα). Patients exhibit growth retardation, delayed bone development, anemia, and bradycardia. By using mouse models of RTHα, much has been learned about the molecular actions of TRα1 mutants that underlie these abnormalities in adults. Using zebrafish models of RTHα that we have recently created, we aimed to understand how TRα1 mutants affect the heart function during this period. Methods: In contrast to human and mice, the thra gene is duplicated, thraa and thrab, in zebrafish. Using CRISPR/Cas9-mediated targeted mutagenesis, we created C-terminal mutations in each of two duplicated thra genes in zebrafish (thraa 8-bp insertion or thrab 1-bp insertion mutations). We recently showed that these mutant fish faithfully recapitulated growth retardation as found in patients and thra mutant mice. In the present study, we used histological analysis, gene expression profiles, confocal fluorescence, and transmission electron microscopy (TEM) to comprehensively analyze the phenotypic characteristics of mutant fish heart during development. Results: We found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and the decreased circulating blood speed and reduced expression of contractile genes indicated weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days postfertilization (juveniles). Furthermore, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by TEM, suggesting that the abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish. Conclusions: Using a zebrafish model of RTHα, the present study demonstrated for the first time that TRα1 mutants could act to cause abnormal heart structure, weaken contractility, and disrupt sarcomere organization that affect heart functions. These findings provide new insights into the bradycardia found in RTHα patients.

Project description:High throughput in vitro, in silico, and computational approaches have identified numerous environmental chemicals that interfere with thyroid hormone (TH) activity, and it is posited that human exposures to such chemicals are a contributing factor to neurodevelopmental disorders. However, whether hits in screens of TH activity are predictive of developmental neurotoxicity (DNT) has yet to be systematically addressed. The zebrafish has been proposed as a second tier model for assessing the in vivo DNT potential of TH active chemicals. As an initial evaluation of the feasibility of this proposal, we determined whether an endpoint often used to assess DNT in larval zebrafish, specifically photomotor behavior, is altered by experimentally induced hyper- and hypothyroidism. Developmental hyperthyroidism was simulated by static waterborne exposure of zebrafish to varying concentrations (3-300?nM) of thyroxine (T4) or triiodothyronine (T3) beginning at 6?h post-fertilization (hpf) and continuing through 5 days post-fertilization (dpf). Teratogenic effects and lethality were observed at 4 and 5 dpf in fish exposed to T4 or T3 at concentrations >30 nM. However, as early as 3 dpf, T4 (> 3 nM) and T3 (> 10 nM) significantly increased swimming activity triggered by sudden changes from light to dark, particularly during the second dark period (Dark 2). Conversely, developmental hypothyroidism, which was induced by treatment with 6-propyl-2-thiouracil (PTU), morpholino knockdown of the TH transporter mct8, or ablation of thyroid follicles in adult females prior to spawning, generally decreased swimming activity during dark periods, although effects did vary across test days. All effects of developmental hypothyroidism on photomotor behavior occurred independent of teratogenic effects and were most robust during Dark 2. Treatment with the T4 analog, Tetrac, restored photomotor response in mct8 morphants to control levels. Collectively, these findings suggest that while the sensitivity of photomotor behavior in larval zebrafish to detect TH disruption is influenced by test parameters, this test can distinguish between TH promoting and TH blocking activity and may be useful for assessing the DNT potential of TH-active chemicals.

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Anatomical Assessment of the Adult Skeleton of Zebrafish Reared Under Different Thyroid Hormone Profiles.

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Anatomical Assessment of the Adult Skeleton of Zebrafish Reared Under Different Thyroid Hormone Profiles.

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