Abstract
Thyroid hormone (TH) balance is essential for vertebrate development. Deiodinase type 1 (D1) and type 2 (D2) increase and deiodinase type 3 (D3) decreases local intracellular levels of T3, the most important active TH. The role of deiodinase-mediated TH effects in early vertebrate development is only partially understood. Therefore, we investigated the role of deiodinases during early development of zebrafish until 96 hours post fertilization at the level of the transcriptome (microarray), biochemistry, morphology and physiology using morpholino (MO) knockdown. Knockdown of D1+D2 (D1D2MO) and knockdown of D3 (D3MO) both resulted in transcriptional regulation of energy metabolism and (muscle) development in abdomen and tail, together with reduced growth, impaired swim bladder inflation, reduced protein content and reduced motility. The reduced growth and impaired swim bladder inflation in D1D2MO could be due to lower levels of T3 which is known to drive growth and development. The pronounced upregulation of a large number of transcripts coding for key proteins in ATP-producing pathways in D1D2MO could reflect a compensatory response to a decreased metabolic rate, also typically linked to hypothyroidism. Compared to D1D2MO, the effects were more pronounced or more frequent in D3MO, in which hyperthyroidism is expected. More specifically, increased heart rate, delayed hatching and increased carbohydrate content were observed only in D3MO. An increase of the metabolic rate, a decrease of the metabolic efficiency and a stimulation of gluconeogenesis using amino acids as substrates may have been involved in the observed reduced protein content, growth and motility in D3MO larvae. Furthermore, expression of transcripts involved in purine metabolism coupled to vision was decreased in both knockdown conditions, suggesting that both may impair vision. This study provides new insights, not only into the role of deiodinases, but also into the importance of a correct TH balance during vertebrate embryonic development.
Highlights
Thyroid hormones (THs) play an important role in a wide range of biological processes in vertebrates including growth, development, reproduction, cardiac function, thermoregulation, response to injury, tissue repair and homeostasis [1,2,3,4]
Our previous studies showed that both D2MO and D1D2MO phenotypes could be largely rescued by T3 supplementation [11,14] and that the phenotype of D3MO zebrafish embryos could be partially mimicked by T3 supplementation and rescued by injection of human deiodinase type 3 (D3) mRNA [10]
In order to relate transcriptional effects to phenotypic effects, we studied the phenotypes of D1D2MO and D3MO embryos and larvae at different developmental time points spanning from 24 hpf to 96 hpf
Summary
Thyroid hormones (THs) play an important role in a wide range of biological processes in vertebrates including growth, development, reproduction, cardiac function, thermoregulation, response to injury, tissue repair and homeostasis [1,2,3,4]. Three deiodinases (D) have been characterized that locally activate or inactivate THs and are important mediators of TH action. As well as in many other studies, it has been reported that deiodinases play an essential role in vertebrate development by regulating local TH levels during crucial stages of embryonic development [8,9,10,11,12]. In oviparous species, embryos fully rely on a fixed amount of maternal THs deposited in the yolk until activation of the embryonic thyroid; for zebrafish this occurs around 72 hpf (hours post fertilization) [16]. Deiodinases are essential for the activation of maternally transferred TH This early developmental period is the focus of the current study, and the transcriptional responses are investigated at 72 hpf
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