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Maternal thyroid hormones role in zebrafish neural development
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In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity
Publication . Silva, Nadia; Campinho, Marco António
Maternally 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.
Corrigendum: in a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity
Publication . Silva, Nadia; Campinho, Marco António
Maternal thyroid hormone is required to develop the hindbrain vasculature in zebrafish
Publication . Trindade, Marlene; Silva, Nádia; Rodrigues, Joana; Kawakami, Koichi; Campinho, Marco António
Thyroid hormone (TH) signaling is important and necessary for proper neurodevelopment. Inadequate levels of maternally derived THs (MTH) supply affect target gene expression profiles, which are fundamental for the brain’s normal growth, maturation, and function. The monocarboxylate transporter 8 (SLC16A2, MCT8) is the main TH transporter present in the brain during embryonic development, and mutations in this transporter lead to a rare and debilitating human condition known as the Allan-Herndon-Dudley Syndrome (AHDS). This mutation affects the capacity for intracellular transport of the hormone, leading to impaired brain development that constitutes the main pathophysiological basis of AHDS. Like humans, zebrafish embryos express slc16a2 that transports exclusively T3 at zebrafish physiological temperature. Studies in zebrafish Mct8 knockdown (KD) models found impaired hindbrain vasculature development. Here, using zebrafish Mct8 KD and knockout (KO) models, we shed light on the maternal T3 (MT3)-dependent developmental mechanism behind hindbrain vasculature development. We first demonstrate that MT3-regulates hindbrain vegfaa expression. We provide evidence that hindbrain neurons are not the source of vegfaa, instead, restricted pax6a+ neuroprogenitor cells (NPCs) instruct central arteries (CtAs) ingression into the hindbrain. Therefore, MT3 acts as an integrator, providing the regulatory cues necessary for the timely ingression of the CtAs into the hindbrain.
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Fundação para a Ciência e a Tecnologia
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SFRH/BD/111226/2015