Diverse functions of retinoic acid in brain vascular development.
Open accessAbstract
UNLABELLED: 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. SIGNIFICANCE STATEMENT: Work presented here provides novel insight into important yet little understood aspects of brain vascular development, implicating for the first time a factor upstream of endothelial WNT signaling. We show that RA is permissive for cerebrovascular growth via suppression of WNT inhibitor expression in the neocortex. RA also functions cell-autonomously in brain endothelial cells to modulate WNT signaling and its downstream target, Sox17. The significance of this is although endothelial WNT signaling is required for neurovascular development, too much endothelial WNT signaling, as well as overexpression of its target Sox17, are detrimental. Therefore, RA may act as a "brake" on endothelial WNT signaling and Sox17 to ensure normal brain vascular development.
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Production of RA by the arachnoid layers critically regulates brain and neurovascular development.
“Production of RA by the arachnoid layers critically regulates brain and neurovascular development (Siegenthaler et al., 2009; Choi et al., 2014; Bonney et al., 2016; Mishra et al., 2016; Haushalter et al., 2017).”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Bonney et al., 2016
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Zhao, Y., Vuckovic, M. G., Yoo, H. S., Fox, N., Rodriguez, A., McKessy, K., & Napoli, J. L. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101101 · Cited by 11 · see citing works
Blood–Brain Barrier: Physiological and Functional Considerations
Rosas-Hernández, H., Cuevas, E., Lantz, S. M., Imam, S. Z., Paule, M. G., & Ali, S. F. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809405-1.00020-1 · Cited by 7 · see citing works
Retinoic acid signaling in mouse retina endothelial cells is required for early angiogenic growth
Como, C. N., Cervantes, C., Pawlikowski, B. T., & Siegenthaler, J. A. (2022) · Differentiation · doi:10.1016/j.diff.2022.12.002 · Cited by 5 · see citing works
RYBP regulates Pax6 during in vitro neural differentiation of mouse embryonic stem cells
Sutus, E., Henry, S., Adorján, L., Kovács, G. E., & Pirity, M. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-06228-1 · Cited by 4 · see citing works
Human In Vitro Blood-Brain Barrier Models Derived from Stem Cells
Foreman, K. L., Palecek, S. P., & Shusta, E. V. (2022) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-3-030-88773-5_9 · Cited by 2 · see citing works
Wang, J., Yin, Y., Qiu, J., Wu, X., Dong, H., Chen, R., Xing, H., & Huang, L. (2018) · Oncotarget · doi:10.18632/oncotarget.24096 · Cited by 1 · see citing works
Meningioma Development: Meningeal Embryology and Tumorigenesis
Himič, V., Jeyaretna, D. S., & Fountain, D. M. (2024) · Springer eBooks · doi:10.1007/978-3-031-76680-0_5 · Cited by 1 · see citing works
Bonney, S. K., Mishra, S., Pleasure, S. J., & Siegenthaler, J. A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814405-3.00043-6
- Authors
- Bonney, S., Harrison-Uy, S., Mishra, S., MacPherson, A. M., Choe, Y., Li, D., Jaminet, S.-C., Fruttiger, M., Pleasure, S. J., & Siegenthaler, J. A.
- Affiliations
- University of Colorado Anschutz (US)
- University of California, San Francisco (US)
- Beth Israel Deaconess Medical Center (US)
- University College London (GB)
- ORCID
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-07-20
- Volume
- 36
- Issue
- 29
- Pages
- 7786-7801
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4951581
- OpenAlex
- W2500771105
- Cited by
- 40
- References
- 57
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 6 · 2023: 2 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 2
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (K99-R00)
- National Institute of Mental Health (R01MH105360)
- National Institute on Drug Abuse (R01DA017627)
- National Institute of Neurological Disorders and Stroke (R00NS070920, R01NS098273)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- retinoic acid, cerebrovascular development, Wnt inhibitors, SOX17, blood-brain barrier, neocortex, brain endothelial cells, non-cell-autonomous signaling, cell-autonomous signaling, RDH10, neurovascular development
- MeSH terms
- Retinoic Acid Receptor alpha, Age Factors, Alcohol Oxidoreductases, Animals, beta-Galactosidase, Brain, Cell Differentiation, Cells, Cultured, Cerebral Ventricles, Embryo, Mammalian, Humans, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Tretinoin, Gene Expression Regulation, Developmental, Ephrins, Endothelial Cells, beta Catenin, Mice, Wnt Signaling Pathway
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