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Diverse Functions of Retinoic Acid in Brain Vascular Development

Bonney, S; Harrison-Uy, S; Mishra, S; MacPherson, AM; Choe, Y; Li, D; Jaminet, S-C; ... Siegenthaler, JA; + view all (2016) Diverse Functions of Retinoic Acid in Brain Vascular Development. JNeurosci , 36 (29) pp. 7786-7801. 10.1523/JNEUROSCI.3952-15.2016. Green open access

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Abstract

As neural structures grow in size and increase metabolic demand, the CNS vasculature undergoes extensive growth, remodeling, and maturation. Signals from neural tissue act on endothelial cells to stimulate blood vessel ingression, vessel patterning, and acquisition of mature brain vascular traits, most notably the blood–brain barrier. Using mouse genetic and in vitro approaches, we identified retinoic acid (RA) as an important regulator of brain vascular development via non-cell-autonomous and cell-autonomous regulation of endothelial WNT signaling. Our analysis of globally RA-deficient embryos (Rdh10 mutants) points to an important, non-cell-autonomous function for RA in the development of the vasculature in the neocortex. We demonstrate that Rdh10 mutants have severe defects in cerebrovascular development and that this phenotype correlates with near absence of endothelial WNT signaling, specifically in the cerebrovasculature, and substantially elevated expression of WNT inhibitors in the neocortex. We show that RA can suppress the expression of WNT inhibitors in neocortical progenitors. Analysis of vasculature in non-neocortical brain regions suggested that RA may have a separate, cell-autonomous function in brain endothelial cells to inhibit WNT signaling. Using both gain and loss of RA signaling approaches, we show that RA signaling in brain endothelial cells can inhibit WNT-β-catenin transcriptional activity and that this is required to moderate the expression of WNT target Sox17. From this, a model emerges in which RA acts upstream of the WNT pathway via non-cell-autonomous and cell-autonomous mechanisms to ensure the formation of an adequate and stable brain vascular plexus.

Type: Article
Title: Diverse Functions of Retinoic Acid in Brain Vascular Development
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.3952-15.2016
Publisher version: http://dx.doi.org/10.1523/JNEUROSCI.3952-15.2016
Language: English
Additional information: © 2016. This manuscript version is published under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0). This licence allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licences are available at http://creativecommons.org/licenses/by-nc-sa/3.0. Access may be initially restricted by the publisher.
Keywords: Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, brain vascular development, cerebrovasculature, endothelial cell, retinoic acid, VEGF, WNT, CNS, endothelial-cell proliferation, nuclear receptors, embryonic mouse, growth-factor, barrier, angiogenesis, differentiation, expression, defects
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1508960
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