Abstract
Thyroid hormones (TH) are crucial for brain development; their deficiency during neurodevelopment impairs neural cell differentiation and causes irreversible neurological alterations. Understanding TH action, and in particular the mechanisms regulating TH availability in the prenatal human brain is essential to design therapeutic strategies for neurological diseases due to impaired TH signaling during neurodevelopment. We aimed at the identification of cells involved in the regulation of TH availability in the human brain at fetal stages. To this end, we studied the distribution of the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1), as well as the TH-metabolizing enzymes types 2 and 3 deiodinases (DIO2 and DIO3). Paraffin-embedded human brain sections obtained from necropsies of thirteen fetuses from 14 to 38 gestational weeks were analyzed by immunohistochemistry and in situ hybridization. We found these proteins localized along radial glial cells, in brain barriers, in Cajal-Retzius cells, in migrating fibers of the brainstem and in some neurons and glial cells with particular and complex spatiotemporal patterns. Our findings point to an important role of radial glia in controlling TH delivery and metabolism and suggest two additional novel pathways for TH availability in the prenatal human brain: the outer, and the inner cerebrospinal fluid–brain barriers. Based on our data we propose a model of TH availability for neural cells in the human prenatal brain in which several cell types have the ability to autonomously control the required TH content.
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Acknowledgements
We are very grateful to the subjects’ parents who gave their consent to using the brain tissues for this investigation. We are also indebted to the IdiPAZ Biobank integrated into the Spanish Biobank Network (http://www.redbiobancos.es) and the Wolfson Medical Center, Holon, Israel, and the Sackler School of Medicine, Tel Aviv, Israel for the generous gifts of clinical samples used in this work. The IdiPAZ Biobank is supported by Instituto de Salud Carlos III, Spanish Health Ministry (Retic RD09/0076/00073) and Farmaindustria, through the Cooperation Program in Clinical and Translational Research of the Community of Madrid. We thank Drs. Soledad Bárez-López, José Miguel Cosgaya, Estrella Rausell and Ana Montero-Pedrazuela for the careful reading of the manuscript and their helpful suggestions, and Javier Pérez for his help on the artwork. This work was supported by Grants from the Spanish Plan Nacional de I+D+i (Grant numbers SAF2014-54919-R and SAF2017-86342-R to A.GF and J.B), and the Center for Biomedical Research on Rare Diseases (Ciberer), Instituto de Salud Carlos III, Madrid, Spain and the Sherman Foundation (OTR02211 to A.GF). D.LE is a recipient of a fellowship from “Fellowship Training Program for Advanced Human Capital, BECAS CHILE” from the National Commission for Scientific and Technological Research (CONICYT), Gobierno de Chile. The cost of this publication has been paid in part by FEDER funds.
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Online Supplementary Resource 2 Negative MCT8, OATP1C1, DIO2 and DIO3 immunostaining in fetal cerebral barriers.
Representative photomicrographs showing immunohistochemical staining (brown color) of MCT8 (a, f and k), OATP1C1 (b, g and l), DIO2 (c, h and m), DIO3 (d, i and n), and the control staining without primary antibodies (e, j and o) in the BBB (a–e), choroid plexus (f–j) and ependymal epithelium (k–o) in control fetuses at GW30 (a–e) and GW38 (f–o). Tissue sections were not counterstained. Note the immunoreactivity of each protein associated with blood vessels (arrowheads), epithelial cells of choroid plexus (arrowheads), and ependymal epithelium (arrowheads), compared to the negative control which does not present background staining. Scale bar represents 364 µm (a–e) and 182 µm (f–o) (TIFF 13,753 kb)
Online Supplementary Resource 3 MCT8 immunostaining in the cortical white matter in control and MCT8-deficient fetus
. Low- and high-power representative photomicrographs showing MCT8 immunostaining (brown color) in the occipital white matter in control (a and c) and MCT8-deficient (b and d) fetuses at GW30. Tissue sections were also counterstained with hematoxylin (blue color). Arrowheads point to BBB vessels. Note the very weak, almost absent, MCT8 immunostaining associated with blood vessels in the MCT8-deficient fetus. Scale bar represents 150 µm (a, b) and 30 µm (c, d) (TIFF 4641 kb)
Online Supplementary Resource 8 GFAP, vimentin and nestin immunostaining in the radial glia basal processes.
Representative photomicrographs showing GFAP (a, d, and g), vimentin (b, e, and h) and nestin (c, f, and i) immunohistochemistry (brown color), in the cortical plate (a–c), intermediate zone (d–f) and ventricular zone (g–i) in control fetuses at GW14 (c, f, and i) and GW20 (a, b, d, e, g, and h). Tissue sections were also counterstained with hematoxylin (blue color). Note the strong immunoreactivity of all the proteins in RG basal processes (arrowheads) and in RG cytoplasm (arrows). Scale bar represents 22 µm (TIFF 20,058 kb)
Online Supplementary Resource 9 Transporter and deiodinase expression in isolated single radial glia cells of the developing human brain.
Data extracted from a published database on transcriptomic analyses of single RG microdissected from GW16-18 human fetal cortex (Pollen et al. 2015) (PDF 822 kb)
Online Supplementary Resource 10 OATP1C1, DIO2 and DIO3 immunostaining in cortical plate neural cells and radial glia.
Representative photomicrographs showing OATP1C1 (a and d), DIO2 (b and e) and DIO3 (c and f) immunohistochemistry (brown color) in cerebral cortex fetuses at GW20. d, e, and f correspond to high-magnification images from a, b, and c, respectively. Tissue sections were also counterstained with hematoxylin (blue color). Arrowheads point to RG basal processes. Abbreviations: I: layer I; Cp: Cortical plate; Sp: Subplate. Scale bar represents 240 µm (a–c) and 24 µm (d-f) (TIFF 24,351 kb)
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López-Espíndola, D., García-Aldea, Á., Gómez de la Riva, I. et al. Thyroid hormone availability in the human fetal brain: novel entry pathways and role of radial glia. Brain Struct Funct 224, 2103–2119 (2019). https://doi.org/10.1007/s00429-019-01896-8
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DOI: https://doi.org/10.1007/s00429-019-01896-8