Mfsd2a is critical for the formation and function of the blood-brain barrier
Open accessAbstract
The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the 'blood-brain barrier' (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux. Although BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS. A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here we identify mechanisms governing the establishment of a functional BBB. First, using a novel tracer-injection method for embryos, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a (Mfsd2a) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic stages through to adulthood, but the normal patterning of vascular networks is maintained. Electron microscopy examination reveals a dramatic increase in CNS-endothelial-cell vesicular transcytosis in Mfsd2a(-/-) mice, without obvious tight-junction defects. Finally we show that Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify Mfsd2a as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Furthermore, our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery.
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Knockout of murine Mfsd2a gene results in diminished brain uptake of docosahexaenoic acid (DHA) in the form of lysophosphatidylcholine and leads to dysregulated caveolae-mediated transcellular trafficking across the BBB causing BBB breakdown.
“whereas knockout of murine Mfsd2a gene results in not only diminished brain uptake of docosahexaenoic acid (DHA) in the form of lysophosphatidylcholine, but also leads to dysregulated caveolae-mediated transcellular trafficking across the BBB causing BBB breakdown (21, 62, 684).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [62]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMfsd2a-deficient mice exhibit impaired brain uptake of lysophosphatidylcholine-long fatty acyl chains and develop blood-brain barrier breakdown, accompanied by neuronal loss in hippocampus and cerebellum causing microcephaly and behavioral deficits.
“Mfsd2a -deficient mice exhibit impaired brain uptake of lysophosphatidylcholine-long fatty acyl chains and develop BBB breakdown, which is accompanied by neuronal loss in hippocampus and cerebellum causing microcephaly and behavioral deficits (62, 63, 430, 684).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [62]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredBrain endothelial specific or enriched transporters are often indispensable for BBB barriergenesis, as for example, GLUT1, MFSD2A, and MCT8.
“Brain endothelial specific or enriched transporters are often indispensable for BBB barriergenesis, as for example, the glucose transporter-1 (GLUT1) (649), sodium-dependent lysophosphatidylcholine (LPC) symporter, the major facilitator superfamily (MFS) domain-containing protein 2a (MFSD2A) (62), and monocarboxylic acid transporter MCT8 (611).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [62]
In the brain, MFSD2a is exclusively expressed in brain endothelium.
“In the brain, MFSD2a is exclusively expressed in brain endothelium and is required for proper BBB development and functional integrity (62).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [62]
MFSD2a is required for proper blood-brain barrier development and functional integrity.
“In the brain, MFSD2a is exclusively expressed in brain endothelium and is required for proper BBB development and functional integrity (62).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [62]
Murine Mfsd2a is expressed in the brain exclusively in endothelium of the blood-brain barrier.
“As in humans, murine Mfsd2a is expressed in the brain exclusively in endothelium of the BBB (62, 430).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [62]
Non-capillary endothelial cells in the embryonic ChP expressed BBB markers Cldn5 and Mfsd2a, even though the ChP is recognized to lack a classic BBB.
“Specifically, non-capillary endothelial cells in the embryonic ChP expressed BBB markers (Cldn5 and Mfsd2a, Topic 11) (Figure 6A), even though the ChP is recognized to lack a classic BBB (Ben-Zvi et al., 2014; Saunders et al., 2018b).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Ben-Zvi et al., 2014
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- Authors
- Ben-Zvi, A., Lacoste, B., Kur, E., Andreone, B. J., Mayshar, Y., Yan, H., & Gu, C.
- Affiliations
- Harvard University (US)
- Corresponding author
- Gu, Chenghua
- Venue
- Nature
- Published
- 2014-05-14
- Volume
- 509
- Issue
- 7501
- Pages
- 507-511
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4134871
- OpenAlex
- W1968060691
- Cited by
- 1,037
- References
- 31
- Citations by year
- 2026: 92 · 2025: 101 · 2024: 97 · 2023: 95 · 2022: 119 · 2021: 120 · 2020: 111 · 2019: 61 · 2018: 72 · 2017: 67 · 2016: 36 · 2015: 42 · 2014: 23
- FWCI
- 29.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Mental Health (5T32MH20017-15, T32MH020017)
- National Institute of Neurological Disorders and Stroke (R01NS064583, P30NS072030)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- MFSD2A, blood-brain barrier, major facilitator superfamily, brain endothelial cells, pericytes, transcytosis, omega fatty acids, brain development, brain drug delivery, tight junctions
- MeSH terms
- Animals, Blood Vessels, Blood-Brain Barrier, Cerebral Cortex, Female, Male, Drug Delivery Systems, Neovascularization, Physiologic, Tight Junctions, Pericytes, Gene Expression Profiling, Membrane Transport Proteins, Symporters, Endothelial Cells, Mice, Transcytosis, Spatio-Temporal Analysis
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