Percorrer por autor "Silva, Nádia Margarida Rosário"
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- Maternal thyroid hormones role in Zebrafish neural developmentPublication . Silva, Nádia Margarida Rosário; Campinho, Marco António de Jesus; Power, DeborahThyroid hormones (TH) are essential for proper embryonic development of the central nervous system. During this period maternal supply of TH is the only source of these hormones to the embryo. Using a zebrafish MCT8 knockdown model, with consequent inhibition of maternal thyroid hormones (MTH) uptake to the target cells, the aim of this thesis is to start a comprehensive understanding of the role of MTH during embryonic neural development. We characterised the transcriptome in 25hpf CTRL and MCT8MO zebrafish embryos and found 4,343 differentially expressed genes. Reactome analysis show that MTH regulate the expression of core developmental pathways such as NOTCH, SHH and WNT. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. We identified a series of genes involved in several key neurogenic processes to be modulated by MTH. By analysing these genes by qPCR in a temporal series, from the start of segmentation through hatching, we determined the developmental time-window where MTH are required for appropriate CNS development. We show MTH are involved in the regulation of NOTCH pathway components such as notch1a, dla, dld, her2 and her4 during neurogenesis, whereas neuroectodermal genes are not affected. Response to MTH begins at 12hpf, and the time window between 22-25hpf is particularly sensitive to MTH action. Overall, these results, show that MTH is not involved in neuroectoderm specification nor CNS compartmentalisation but stress the involvement of MTH in the early stages of neurogenesis by promoting the maintenance of specific neural progenitor populations. Analyzing the cytoarchitecture of the spinal cord we found that by the end of embryogenesis cells populating the spinal cord of control and MCT8 MO zebrafish are substantially different. Lack of thyroid hormone uptake leads to a generalized disorganization of the neural tissue, together with a decrease in: neural stem cells population, subpopulations of neuron progenitor cells, radial glial cells, mature glial cells and oligodendrocyte precursors, while the primary motor neuron domain was maintained. Colocalization analysis of neural progenitors with thraa, thrab and mct8 allowed identifying cells under the regulation of MTH via MCT8. Survival and proliferation of neural progenitor cells are compromised in MCT8MO, which could later impact on the diversity of neural cell populations obtained in the end of embryogenesis. Analysis of cell autonomous Notch activation showed it cannot rescue the phenotype induced by the lack of MTH demonstrating the niche importance in the regulation of TH action. Given that MTH regulate several important morphogenetic pathways it is likely that its action occurs as an integrator enabling an adequate equilibrium between all these signals in a time a context dependent manner. MTH actions are reflected on the timely development of neurons and glial cells. It is of great interest to continue to explore the significance of these findings to further clarify the genetic and cellular causes underlying human AHDS syndrome. In conclusion with this work, we show that thyroid hormone transferred from the mother to the embryo allows the enrichment of neural progenitor pools and the generation of cell diversity necessary to produce a fully functional central nervous tissue.