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Retinoic Acid Induces Blood–Brain Barrier Development
Open accessAbstract
The blood–brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of the BBB possess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB endothelial phenotype is induced during neurovascular development by surrounding cells of the CNS. However, the molecular differentiation of the BBB endothelium remains poorly understood. Retinoic acid (RA) plays a crucial role in the brain during embryogenesis. Because radial glial cells supply the brain with RA during the developmental cascade and associate closely with the developing vasculature, we hypothesize that RA is important for the induction of BBB properties in brain ECs. Analysis of human postmortem fetal brain tissue shows that the enzyme mainly responsible for RA synthesis, retinaldehyde dehydrogenase, is expressed by radial glial cells. In addition, the most important receptor for RA-driven signaling in the CNS, RA-receptor β (RARβ), is markedly expressed by the developing brain vasculature. Our findings have been further corroborated by in vitro experiments showing RA- and RARβ-dependent induction of different aspects of the brain EC barrier. Finally, pharmacologic inhibition of RAR activation during the differentiation of the murine BBB resulted in the leakage of a fluorescent tracer as well as serum proteins into the developing brain and reduced the expression levels of important BBB determinants. Together, our results point to an important role for RA in the induction of the BBB during human and mouse development.
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“RA/RAR signaling is critical for BBB differentiation and integrity90.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [90]
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“In vivo, pharmacologic modulation of RAR-b resulted Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020412 11 in a perturbed BBB (Mizee et al. 2013).”
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“Furthermore, hPSCderived brain endothelial cells exhibit significantly increased barrier phenotype in response to retinoic acid (TEER increases up to 2940 800 cm(2)),(256) a hormone implicated in BBB regulation.(42,272,273) The stem cell-based models could additionally be used to interrogate other signaling pathways a…”
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Metadata
- Authors
- Mizee, M. R., Wooldrik, D., Lakeman, K. A. M., van het Hof, B., Drexhage, J. A. R., Geerts, D., Bugiani, M., Aronica, E., Mebius, R. E., Prat, A., de Vries, H. E., & Reijerkerk, A.
- Affiliations
- Amsterdam Neuroscience (NL)
- Erasmus MC (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Hôpital Notre-Dame (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-01-23
- Volume
- 33
- Issue
- 4
- Pages
- 1660-1671
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6618717
- OpenAlex
- W1985474890
- Cited by
- 203
- References
- 60
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 13 · 2023: 13 · 2022: 19 · 2021: 19 · 2020: 18 · 2019: 11 · 2018: 17 · 2017: 15 · 2016: 16 · 2015: 26 · 2014: 14 · 2013: 7
- FWCI
- 11.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Top Institute Pharma
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- retinoic acid, blood-brain barrier development, brain endothelial cells, retinoic acid receptor beta, retinaldehyde dehydrogenase, radial glia, neurovascular development, endothelial barrier function, fetal brain
- MeSH terms
- Animals, Blood-Brain Barrier, Cell Differentiation, Cell Line, Fetus, Humans, Immunohistochemistry, Mice, Inbred C57BL, Neuroglia, Tretinoin, Blotting, Western, Signal Transduction, Gene Expression Regulation, Developmental, Endothelial Cells, Mice, Real-Time Polymerase Chain Reaction
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