The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Astrocyte-endothelial interactions at the blood-brain barrier
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1824 · Cited by 5,595
Structure and function of the blood–brain barrier
Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R., & Begley, D. J. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.07.030 · Cited by 5,185
Pericytes regulate the blood–brain barrier
Armulik, A., Genové, G., Mäe, M., Nisancioglu, M. H., Wallgard, E., Niaudet, C., He, L., Norlin, J., Lindblom, P., Strittmatter, K., et al. (2010) · Nature · doi:10.1038/nature09522 · Cited by 2,843
Molecular regulation of vessel maturation
Jain, R. K. (2003) · Nature Medicine · doi:10.1038/nm0603-685 · Cited by 2,594
Pericytes are required for blood–brain barrier integrity during embryogenesis
Daneman, R., Zhou, L., Kebede, A. A., & Barres, B. A. (2010) · Nature · doi:10.1038/nature09513 · Cited by 2,128
Phenotypic Heterogeneity of the Endothelium
Aird, W. C. (2007) · Circulation Research · doi:10.1161/01.res.0000255691.76142.4a · Cited by 1,824
Blood‐brain barrier‐specific properties of a human adult brain endothelial cell line
Weksler, B. B., Subileau, E.-A., Perrière, N., Charneau, P., Holloway, K. E., Leveque, M., Tricoire-Leignel, H., Nicotra, A., Bourdoulous, S., Turowski, P., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-3458fje · Cited by 1,325
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293
Phenotypic Heterogeneity of the Endothelium
Aird, W. C. (2007) · Circulation Research · doi:10.1161/01.res.0000255690.03436.ae · Cited by 1,288
Retinoic Acid Synthesis and Signaling during Early Organogenesis
Duester, G. (2008) · Cell · doi:10.1016/j.cell.2008.09.002 · Cited by 1,098
Cited by
Sorted by citations
Daneman, R., & Prat, A. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020412 · Cited by 3,437
“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).”
BackgroundSelf-citationMfsd2a is critical for the formation and function of the blood-brain barrier
Ben-Zvi, A., Lacoste, B., Kur, E., Andreone, B. J., Mayshar, Y., Yan, H., & Gu, C. (2014) · Nature · doi:10.1038/nature13324 · Cited by 1,037
Overcoming the blood–brain tumor barrier for effective glioblastoma treatment
van Tellingen, O., Yetkin-Arik, B., de Gooijer, M. C., Wesseling, P., Wurdinger, T., & de Vries, H. E. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.02.002 · Cited by 1,035
Helms, H. C., Abbott, N. J., Burek, M., Cecchelli, R., Couraud, P.-O., Deli, M. A., Förster, C., Galla, H. J., Romero, I. A., Shusta, E. V., et al. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16630991 · Cited by 843
“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…”
BackgroundThe dynamic blood–brain barrier
Keaney, J., & Campbell, M. (2015) · The FEBS Journal · doi:10.1111/febs.13412 · Cited by 616
Brain barriers: Crosstalk between complex tight junctions and adherens junctions
Tietz, S., & Engelhardt, B. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201412147 · Cited by 551
“Radial glial cells in fetal human brain tissue were found to express high levels of the RA-producing enzyme retinaldehyde dehydrogenase 2 (RALDH2) and to tightly associate with the developing brain vasculature expressing the RA receptor during embryogenesis (Mizee et al., 2013).”
BackgroundGlial influence on the blood brain barrier
Alvarez, J. I., Katayama, T., & Prat, A. (2013) · Glia · doi:10.1002/glia.22575 · Cited by 577
“In vivo pharmacologic inhibition of RARb affected the differentiation of the murine vasculature that resulted in a perturbed BBB (Mizee et al., 2013).”
BackgroundSelf-citationLippmann, E. S., Al-Ahmad, A., Azarin, S. M., Palecek, S. P., & Shusta, E. V. (2014) · Scientific Reports · doi:10.1038/srep04160 · Cited by 508
Neuronal regulation of the blood–brain barrier and neurovascular coupling
Kaplan, L., Chow, B. W., & Gu, C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0322-2 · Cited by 455
Good, R. B., Gilbane, A. J., Trinder, S. L., Denton, C. P., Coghlan, G., Abraham, D. J., & Holmes, A. M. (2015) · The American Journal of Pathology · doi:10.1016/j.ajpath.2015.03.019 · Cited by 349
Novel insights into the development and maintenance of the blood-brain barrier
Engelhardt, B., & Liebner, S. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1811-2 · Cited by 313
“In apparent contrast to these observations, vascular sprouts have been observed to be tight for serum proteins from the earliest stages of invasion into the developing CNS (summarized in Saunders et al. 2012).”
BackgroundResultCanfield, S. G., Stebbins, M. J., Morales, B. S., Asai, S. W., Vatine, G. D., Svendsen, C. N., Palecek, S. P., & Shusta, E. V. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13923 · Cited by 250
Michinaga, S., & Koyama, Y. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030571 · Cited by 263
“During BBB differentiation, the inhibition of RAR activation caused leakage of serum proteins into the developing brain, and reduced the expression of BBB determinants [118].”
BackgroundSaunders, N. R., Dreifuss, J.-J., Dzięgielewska, K. M., Johansson, P. A., Habgood, M. D., MøllgÃ¥rd, K., & Bauer, H. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00404 · Cited by 274
Neuronal and vascular interactions
Andreone, B. J., Lacoste, B., & Gu, C. (2015) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071714-033835 · Cited by 256
How Do Immune Cells Support and Shape the Brain in Health, Disease, and Aging?
Schwartz, M., Kipnis, J., Rivest, S., & Prat, A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3241-13.2013 · Cited by 269
“TGF- , neurotrophins, FGFs, and retinoic acid have been identified as factors released by astrocytes that contribute to optimal BBB functioning (Fabry et al., 1995; Koyama et al., 2003; Reuss et al., 2003; Wall, 2003; Koyama et al., 2005; Mizee et al., 2013).”
BackgroundSelf-citationDirected differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells
Qian, T., Maguire, S. E., Canfield, S. G., Bao, X., Olson, W. R., Shusta, E. V., & Palecek, S. P. (2017) · Science Advances · doi:10.1126/sciadv.1701679 · Cited by 254
Development and Function of the Blood-Brain Barrier in the Context of Metabolic Control
Haddad-Tóvolli, R., Dragano, N. R. V., Ramalho, A. F. S., & Velloso, L. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00224 · Cited by 226
“Recent studies have uncovered yet another important role for astrocytes in the production of retinoic acid, which is also necessary for the correct development of BBB vessels (Halilagic et al., 2007; Mizee et al., 2013).”
BackgroundAstrocyte-immune cell interactions in physiology and pathology
Han, R. T., Kim, R. D., Molofsky, A. V., & Liddelow, S. A. (2021) · Immunity · doi:10.1016/j.immuni.2021.01.013 · Cited by 223
Lu, T. M., Houghton, S., Magdeldin, T., Durán, J. G. B., Minotti, A. P., Snead, A. M., Sproul, A. A., Nguyen, D.-H. T., Xiang, J., Fine, H. A., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016950118 · Cited by 224
A Historical Review of Brain Drug Delivery
Pardridge, W. M. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061283 · Cited by 219
The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction
Kugler, E., Greenwood, J., & MacDonald, R. B. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.732820 · Cited by 228
It Takes a Village: Constructing the Neurogenic Niche
Bjornsson, C. S., Apostolopoulou, M., Tian, Y. I., & Temple, S. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.010 · Cited by 228
“RGCs also produce retinoic acid (RA), which acts on the brain vessels and helps develop tight junctions, ensuring BBB function (Mizee et al., 2013).”
BackgroundOrgan-specific protection mediated by cooperation between vascular and epithelial barriers
Spadoni, I., Fornasa, G., & Rescigno, M. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.100 · Cited by 206
Stebbins, M. J., Wilson, H. K., Canfield, S. G., Qian, T., Palecek, S. P., & Shusta, E. V. (2016) · Methods · doi:10.1016/j.ymeth.2015.10.016 · Cited by 179
Activation and Role of Astrocytes in Ischemic Stroke
Shen, X.-Y., Gao, Z.-K., Han, Y., Yuan, M., Guo, Y., & Bi, X. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.755955 · Cited by 198
Marques, A. H., Bjørke-Monsen, A.-L., Teixeira, A. L., & Silverman, M. N. (2015) · Brain Research · doi:10.1016/j.brainres.2014.10.051 · Cited by 166
“In addition, several other vitamins (A and D) andminerals (iron) have been shown to affect brain function (e.g., cell differentiation, neurotrophic factor expression, cytokine regulation, neurotransmitter synthesis) (Eyles et al., 2011; Mizee et al., 2013).”
Glial influences on BBB functions and molecular players in immune cell trafficking
Lécuyer, M., Kébir, H., & Prat, A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.004 · Cited by 166
Self-citationEfflux transporters in blood-brain interfaces of the developing brain
Strazielle, N., & Ghersi‐Egea, J. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00021 · Cited by 168
Blood–brain barrier alterations and their impact on Parkinson’s disease pathogenesis and therapy
Lau, K., Kotzur, R., & Richter, F. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00430-z · Cited by 174
“Moreover, in vitro experiments show that TGF-β and retinoic acid secreted by astrocytes induce P-gp expression and activity [148, 149].”
BackgroundBlood brain barrier: A review of its anatomy and physiology in health and disease
Sharif, Y., Jumah, F., Coplan, L., Krosser, A., Sharif, Κ., & Tubbs, R. S. (2018) · Clinical Anatomy · doi:10.1002/ca.23083 · Cited by 151
“When bound, this causes angioblasts to upregulate VE-cadherin, P-glycoprotein, and ZO-1, collectively resulting in increased vascular integrity (Mizee et al., 2013).”
Biology and Models of the Blood–Brain Barrier
Hajal, C., Roi, B. L., Kamm, R. D., & Maoz, B. M. (2021) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-082120-042814 · Cited by 143
“Then, barriergenesis enables endothelial cells to acquire a full BBB phenotype by increasing their expression of glucose transporter 1 (GLUT-1), claudins, and P-glycoprotein following the sustained secretion of different factors by cells of the CNS, such as platelet-derived growth factor B (PDGF-B) from pericytes (8)…”
BackgroundAdvances and challenges in retinoid delivery systems in regenerative and therapeutic medicine
Ferreira, R., Napoli, J., Enver, T., Bernardino, L., & Ferreira, L. (2020) · Nature Communications · doi:10.1038/s41467-020-18042-2 · Cited by 138
STRA6 is critical for cellular Vitamin A uptake and homeostasis
Amengual, J., Zhang, N., Kemerer, M., Maeda, T., Palczewski, K., & Von Lintig, J. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu258 · Cited by 134
“Hydrocephalus has also been described in patients and experimental animal models exposed to excess and deficient levels of vitamin A (43–46) and the vitamin A derivative retinoic acid was recently implicated as a critical embryonic signal for induction of the blood–brain barrier (31).”
BackgroundModeling the blood–brain barrier: Beyond the endothelial cells
Gastfriend, B. D., Palecek, S. P., & Shusta, E. V. (2017) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2017.11.002 · Cited by 133
Wilson, H. K., Canfield, S. G., Hjortness, M. K., Palecek, S. P., & Shusta, E. V. (2015) · Fluids and Barriers of the CNS · doi:10.1186/s12987-015-0007-9 · Cited by 130
Katt, M. E., Xu, Z. S., Gerecht, S., & Searson, P. C. (2016) · PLOS ONE · doi:10.1371/journal.pone.0152105 · Cited by 129
“As described above, retinoic acid is implicated in the induction of the blood-brain barrier endothelial phenotype during development [45] and Lippmann et al.”
BackgroundMizee, M. R., Nijland, P. G., van der Pol, S. M. A., Drexhage, J., Hof, B. V. H., Mebius, R. E., van der Valk, P., van Horssen, J., Reijerkerk, A., & de Vries, H. E. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1335-6 · Cited by 131
Self-citationGlial-endothelial crosstalk regulates blood–brain barrier function
Cheslow, L., & Alvarez, J. I. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.09.010 · Cited by 118
Canfield, S. G., Stebbins, M. J., Faubion, M. G., Gastfriend, B. D., Palecek, S. P., & Shusta, E. V. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0145-6 · Cited by 114
‘Sealing off the CNS’: cellular and molecular regulation of blood–brain barriergenesis
Siegenthaler, J. A., Sohet, F., & Daneman, R. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.06.006 · Cited by 115
“Astrocytederived retinoic acid (RA) has also recently been implicated in inducing barrier properties in cultured human brain endothelial cells [31 ].”
BackgroundA star is born: new insights into the mechanism of astrogenesis
Kanski, R., van Strien, M. E., van Tijn, P., & Hol, E. M. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1435-9 · Cited by 119
“Reporter mice for RA signaling demonstrate activity early in the developing brain [49–51].”
BackgroundBlood–brain barrier and its function during inflammation and autoimmunity
Sonar, S. A., & Lal, G. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ru1117-428r · Cited by 114
Astrocytes in the regulation of cerebrovascular functions
Cohen‐Salmon, M., Slaoui, L., Mazaré, N., Gilbert, A., Oudart, M., Alvear‐Perez, R., Elorza‐Vidal, X., Chever, O., & Boulay, A. (2021) · Glia · doi:10.1002/glia.23924 · Cited by 93
“bly secreted by the radial glial cells) has also been shown to induce BBB differentiation (Mizee et al., 2013).”
BackgroundBlood‐brain barrier development: Systems modeling and predictive toxicology
Saili, K. S., Zurlinden, T. J., Schwab, A. J., Silvin, A., Baker, N., Hunter, E. S., Ginhoux, F., & Knudsen, T. B. (2017) · Birth Defects Research · doi:10.1002/bdr2.1180 · Cited by 101
“An example of an early differentiation signal is the expression of RALDH1 (ALDH1A1; the enzyme needed to synthesize retinoic acid) by radial glia, which may impact barriergenesis by modulating Wnt signaling (Mizee et al., 2013).”
BackgroundStructure and Function of the Blood–Brain Barrier (BBB)
Benz, F., & Liebner, S. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_404 · Cited by 103
Gullotta, G. S., Costantino, G., Sortino, M. A., & Spampinato, S. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119144 · Cited by 97
“For instance, the morphogen sonic hedgehog (Shh) and retinoic acid reinforce endothelial junctional tightness [45,46].”
BackgroundEndothelial sensing of AHR ligands regulates intestinal homeostasis
Wiggins, B. G., Wang, Y.-F., Burke, A., Grunberg, N., Vlachaki Walker, J. M., Dore, M., Chahrour, C., Pennycook, B. R., Sanchez-Garrido, J., Vernia, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06508-4 · Cited by 89
Maussang, D., Rip, J., van Kregten, J., van den Heuvel, A., van der Pol, S. M. A., van der Boom, B. G., Reijerkerk, A., Chen, L., de Boer, M., Gaillard, P. J., et al. (2016) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2016.09.003 · Cited by 87
Self-citationMantle, J. L., Min, L., & Lee, K. H. (2016) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00818 · Cited by 86
A review on in vitro model of the blood-brain barrier (BBB) based on hCMEC/D3 cells
Qi, D., Lin, H., Hu, B., & Wei, Y. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.04.020 · Cited by 93
Stanimirovic, D. B., Bani‐Yaghoub, M., Perkins, M., & Haqqani, A. S. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.974545 · Cited by 86
“Some brain microenvironment-inducing effects on the BBB phenotype can be recapitulated pharmacologically, by targeting the BEC canonical Wnt pathway [37] or by adding retinoic acid (RA) [38].”
BackgroundVascularized human brain organoids: current possibilities and prospects
Kistemaker, L., van Bodegraven, E. J., de Vries, H. E., & Hol, E. M. (2025) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.11.021 · Cited by 91
Spampinato, S. F., Bortolotto, V., Canonico, P. L., Sortino, M. A., & Grilli, M. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01346 · Cited by 81
The Blood–Brain Barrier: Composition, Properties, and Roles in Brain HealthPreprint
Lacoste, B., Prat, A., Andrade, M. F., & Gu, C. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041422 · Cited by 83
“In vivo, pharmacologic modulation of RAR-β resulted in a perturbed BBB (Mizee et al. 2013).”
Self-citationNayler, S., Agarwal, D., Curion, F., Bowden, R. J., & Becker, E. B. E. (2021) · Scientific Reports · doi:10.1038/s41598-021-91846-4 · Cited by 76
Glycolysis-mediated control of blood-brain barrier development and function
Salmina, A. B., Kuvacheva, N. V., Morgun, A. V., Komleva, Y. K., Пожиленкова, Е. А., Lopatina, O. L., Gorina, Y. V., Таранушенко, Т. Е., & Petrova, L. L. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.04.005 · Cited by 76
Wong, C. T., Wais, J., & Crawford, D. A. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.13028 · Cited by 79
“Astrocyte-derived factors, such as sonic hedgehog (Shh; Alvarez et al., 2011), angiotensinogen (Wosik et al., 2007) and retinoic acid (Mizee et al., 2013), have been shown to play roles in the maintenance and modulation of the expression and polarization of transporter proteins in the BBB (Abbott,…”
BackgroundAragón-González, A., Shaw, P. J., & Ferraiuolo, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315271 · Cited by 73
“Retinoic acid (RA) also contributes to BBB maturation, enhancing expression of AJ and TJ proteins [34].”
BackgroundFate and state transitions during human blood vessel organoid development
Nikolova, M. T., He, Z., Seimiya, M., Jonsson, G., Cao, W., Okuda, R., Wimmer, R., Okamoto, R., Nikoloff, J. M., Dittrich, P. S., et al. (2025) · Cell · doi:10.1016/j.cell.2025.03.037 · Cited by 79
Wilson, H. K., Canfield, S. G., Shusta, E. V., & Palecek, S. P. (2014) · Stem Cells · doi:10.1002/stem.1797 · Cited by 65
Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces
Anbalagan, S., Gordon, L., Blechman, J., Matsuoka, R. L., Rajamannar, P., Wircer, E., Biran, J., Reuveny, A., Leshkowitz, D., Stainier, D. Y. R., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.10.017 · Cited by 64
Developmental regulation of barrier‐ and non‐barrier blood vessels in the CNS
Ben‐Zvi, A., & Liebner, S. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13263 · Cited by 67
Mechanobiology of the blood-brain barrier during development, disease and ageing
Konig, S., Jayarajan, V., Wray, S., Kamm, R. D., & Moeendarbary, E. (2025) · Nature Communications · doi:10.1038/s41467-025-61888-7 · Cited by 72
Retinoic acid ameliorates blood–brain barrier disruption following ischemic stroke in rats
Kong, L., Wang, Y., Wang, X., Wang, X., Zhao, Y., Wang, L., & Chen, Z.-Y. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.05.014 · Cited by 64
Maternal iron deficiency perturbs embryonic cardiovascular development in mice
Kalisch-Smith, J. I., Ved, N., Szumska, D., Munro, J. E., Troup, M., Harris, S., Rodriguez‐Caro, H., Jacquemot, A., Miller, J. J. J. J., Stuart, E. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23660-5 · Cited by 67
Fujihara, J., & Nishimoto, N. (2024) · Current Research in Toxicology · doi:10.1016/j.crtox.2024.100157 · Cited by 62
“Retinoic acid also plays an important role in the development of the BBB in humans and mice (Mizee et al., 2013), and its signaling is a critical process for neurodevelopment (Cho et al., 2021; Menegola et al., 2021).”
BackgroundZhou, Y., Zhang, H., Zheng, B., Ye, L., Zhu, S., Johnson, N. R., Wang, Z., Wei, X., Chen, D., Cao, G., et al. (2015) · International Journal of Biological Sciences · doi:10.7150/ijbs.13229 · Cited by 63
“ECs form a tight structural barrier due to the presence of well-developed tight junction (TJ) proteins on the luminal side of the endothelium that ef- Int.”
BackgroundInfluentialLi, Y., Gao, Y., Cui, T., Yang, T., Liu, L., Li, T., & Chen, J. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479203 · Cited by 63
Praça, C., Rosa, S. C., Sevin, E., Cecchelli, R., Dehouck, M., & Ferreira, L. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.08.002 · Cited by 64
“, 2018), and RA (Lippmann et al., 2014; Qian et al., 2017; Mizee et al., 2013) signaling have been reported as important players in early phases of BBB development.”
BackgroundThe role of the retinoids in schizophrenia: genomic and clinical perspectives
Reay, W. R., & Cairns, M. J. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0566-2 · Cited by 63
Retinoic acid promotes barrier functions in human iPSC-derived intestinal epithelial monolayers
Yamada, S., & Kanda, Y. (2019) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2019.06.012 · Cited by 60
Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases
Maria, A. A., Moreno-Ramos, O. A., & Haider, N. B. (2015) · Journal of Experimental Neuroscience · doi:10.4137/jen.s25480 · Cited by 63
Khosravi-Largani, M., Pourvali‐Talatappeh, P., Rousta, A., Karimi-Kivi, M., Noroozi, E., Mahjoob, A., Asaadi, Y., Shahmohammadi, A., Sadeghi, S., Shakeri, S., et al. (2018) · eNeurologicalSci · doi:10.1016/j.ensci.2018.01.007 · Cited by 59
Deng, J., Yao, H., Wang, T., Deng, J., Liu, D., & Li, X. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.133169 · Cited by 56
Glial regulation of the blood-brain barrier in health and disease
Broux, B., Gowing, E., & Prat, A. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-015-0516-2 · Cited by 53
Self-citationβ-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function
Ziegler, N., Awwad, K., Fißlthaler, B., Reis, M., Devraj, K., Corada, M., Minardi, S. P., Dejana, E., Plate, K. H., Fleming, I., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0148-16.2016 · Cited by 50
“For example, the retinol metabolite retinoic acid (RA) as well as polyunsaturated fatty acids could be shown to support barrier integrity and function, respectively (Pifferi et al., 2007; Mizee et al., 2014).”
BackgroundP2X7 Receptors Mediate Innate Phagocytosis by Human Neural Precursor Cells and Neuroblasts
Lovelace, M. D., Gu, B. J., Eamegdool, S. S., Weible, M. W., Wiley, J. S., Allen, D. G., & Chan‐Ling, T. (2014) · Stem Cells · doi:10.1002/stem.1864 · Cited by 51
The Isolated Brain Microvessel: A Versatile Experimental Model of the Blood-Brain Barrier
Pardridge, W. M. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00398 · Cited by 52
Gadhia, M. M., Cutter, G., Abman, S. H., & Kinsella, J. P. (2014) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2013.11.040 · Cited by 49
Patel, R., & Al-Ahmad, A. J. (2016) · Fluids and Barriers of the CNS · doi:10.1186/s12987-016-0030-5 · Cited by 48
“RA has been documented as a barrier inducer in hCMEC/D3 cell monolayers [30], yet the induction range was much more modest compared to IMR90-derived BMECs.”
BackgroundStebbins, M. J., Lippmann, E. S., Faubion, M. G., Daneman, R., Palecek, S. P., & Shusta, E. V. (2017) · Biotechnology Journal · doi:10.1002/biot.201700093 · Cited by 50
“Neither RA nor retinoid receptor agonists elevated occludin levels, contrasting with previous observations of RAmediated increases in occludin expression in hPSC-derived BMECs and hCMECs treated with RA [10, 14].”
BackgroundResultInfluentialAngiopoietin like-4 as a novel vascular mediator in capillary cerebral amyloid angiopathy
Chakraborty, A., Kamermans, A., van het Hof, B., Castricum, K., Aanhane, E., van Horssen, J., Thijssen, V. L., Scheltens, P., Teunissen, C. E., Fontijn, R. D., et al. (2018) · Brain · doi:10.1093/brain/awy274 · Cited by 45
Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
Reay, W. R., Atkins, J., Quidé, Y., Carr, V. J., Green, M. J., & Cairns, M. J. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0305-0 · Cited by 49
Ridaura, I. E., Sorrentino, S., & Moroni, L. (2021) · Advanced Science · doi:10.1002/advs.202101837 · Cited by 46
Ferreira, R., Fonseca, M. C., Santos, T., Sargento-Freitas, J., Tjeng, R., Paiva, F., Castelo-Branco, M., Ferreira, L. S., & Bernardino, L. (2016) · Nanoscale · doi:10.1039/c5nr09077f · Cited by 44
Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells
Lauschke, K., Frederiksen, L., & Hall, V. J. (2017) · Stem Cells and Development · doi:10.1089/scd.2017.0003 · Cited by 46
“RA is secreted by radial glia during brain development and is crucial for the development of a tight BBB during mouse development as well as in BMEC lines [56].”
The roles of astrocyte in the brain pathologies following ischemic stroke
Sun, L., Zhang, Y., Liu, E., Ma, Q., Manaenko, A., Han, H., & Yan, J. (2018) · Brain Injury · doi:10.1080/02699052.2018.1531311 · Cited by 43
“The astrocyte-derived retinoic acid and vitamin A metabolites also have important effects on the BBB formation and vasculature development (30).”
BackgroundDiverse functions of retinoic acid in brain vascular development.
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. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3952-15.2016 · Cited by 40
Signaling Pathways in Neurovascular Development
Rattner, A., Wang, Y., & Nathans, J. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-111020-102127 · Cited by 48
Retinoic acid signaling in vascular development
Pawlikowski, B. T., Wragge, J., & Siegenthaler, J. A. (2019) · genesis · doi:10.1002/dvg.23287 · Cited by 42
Morphogens and blood-brain barrier function in health and disease
Wevers, N. R., & de Vries, H. E. (2015) · Tissue Barriers · doi:10.1080/21688370.2015.1090524 · Cited by 42
“Treatment with RA increased the expression of TJ proteins and induced high transendothelial electrical resistance (TEER), while decreasing levels of the permeability-inducing factor VEGF-A (vascular endothelial growth factor A).(49) Effects were predominantly mediated by RARb, the most important receptor in CNS specif…”
BackgroundHistorical and current perspectives on blood endothelial cell heterogeneity in the brain
Matsuoka, R. L., Buck, L. D., Vajrala, K. P., Quick, R. E., & Card, O. A. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04403-1 · Cited by 40
The vascular niche in next generation microphysiological systems
Ewald, M. L., Chen, Y.-H., Lee, A. P., & Hughes, C. C. W. (2021) · Lab on a Chip · doi:10.1039/d1lc00530h · Cited by 41
(Re)building the nervous system: A review of neuron–glia interactions from development to disease
Demmings, M. D., Chagas, L. D. S., Traetta, M. E., Rodrigues, R. S., Acutain, M. F., Barykin, E. P., Datusalia, A. K., German‐Castelan, L., Mattera, V. S., Mazengenya, P., et al. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16258 · Cited by 44
“This is a two-way interaction, as ECs can increase glial fibrillary acidic protein (GFAP) expression in radial glia in a VEGF- A-dependent manner, leading to astrocyte differentiation and NVU formation (da Silva et al., 2019 ).”
InfluentialTranscriptional mechanisms coordinating tight junction assembly during epithelial differentiation
Boivin, F. J., & Schmidt-Ott, K. M. (2017) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13367 · Cited by 38
Li, Y., Sun, X., Liu, H., Huang, L. J., Meng, G., Ding, Y., Su, W., Lu, J., Gong, S., Terstappen, G. C., et al. (2019) · Neuroscience Bulletin · doi:10.1007/s12264-019-00384-7 · Cited by 39
Moreno-Ramos, O. A., Olivares, A. M., Haider, N. B., de Autismo, L. C., & Lattig, M. C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135927 · Cited by 39
“6) was selected as the chromatin association target protein since it is known to regulate dorsal and ventral telencephalon development, hippocampal plasticity and brain barrier development [35–38].”
Hemanthakumar, K. A., Fang, S., Anisimov, A., Mäyränpää, M. I., Mervaala, E. M. A., & Kivelä, R. (2021) · eLife · doi:10.7554/elife.62678 · Cited by 39
Zhou, Y., Zheng, B., Ye, L., Zhang, H., Zhu, S., Zheng, X., Xia, Q.-H., He, Z., Wang, Q., Xiao, J., et al. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1756-1 · Cited by 35
Retracted
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
