Abstract
Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.
Highlights
In tetrapods thyroid hormones (THs) have a key role in the development of the brain[1,2,3] and in rodents multiple components of the thyroid cellular signalling pathway and T3-induced gene expression[4,5] occur[6]
This has been clearly demonstrated by studies showing that monocarboxylic acid transporter 8 (MCT8) mutations affect transporter characteristics and Thyroid hormones (THs) transport efficiency, giving rise to the phenotypic variability observed in Allan-Herndon-Dudley syndrome (AHDS) patients[25,30,31]
The only known function of MCT8 is facilitated cellular transport of iodothyronines across the plasma membrane and no other substrates have been described in vertebrates[32,33] and a recent study confirmed that MCT8 lacks constitutive activity[34]
Summary
In tetrapods thyroid hormones (THs) have a key role in the development of the brain[1,2,3] and in rodents multiple components of the thyroid cellular signalling pathway and T3-induced gene expression[4,5] occur[6]. The evidence indicates that TH signalling in developing rodent brain cells acts when T3 binds to thyroid hormone nuclear receptors and transactivate or represses gene expression. Evidence from several teleost species indicate that MTHs are deposited in eggs and that[9,10,11] thyroid hormone receptors (TRs) are expressed during early embryonic development[10,12,13,14,15]. The evidence from the zebrafish MCT8 knockdown model indicates that maternal THs in teleost eggs have an essential role in neural development. Expressed neural genes were mapped in situ in embryos and cells under the regulation of MTHs during zebrafish development were identified
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