The Mouse Blood-Brain Barrier Transcriptome: A New Resource for Understanding the Development and Function of Brain Endothelial Cells
Open accessAbstract
The blood-brain barrier (BBB) maintains brain homeostasis and limits the entry of toxins and pathogens into the brain. Despite its importance, little is known about the molecular mechanisms regulating the development and function of this crucial barrier. In this study we have developed methods to highly purify and gene profile endothelial cells from different tissues, and by comparing the transcriptional profile of brain endothelial cells with those purified from the liver and lung, we have generated a comprehensive resource of transcripts that are enriched in the BBB forming endothelial cells of the brain. Through this comparison we have identified novel tight junction proteins, transporters, metabolic enzymes, signaling components, and unknown transcripts whose expression is enriched in central nervous system (CNS) endothelial cells. This analysis has identified that RXRalpha signaling cascade is specifically enriched at the BBB, implicating this pathway in regulating this vital barrier. This dataset provides a resource for understanding CNS endothelial cells and their interaction with neural and hematogenous cells.
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Several amino acid transporters have been identified in pericytes, including high-affinity excitatory amino acid transporter EAAT2, sodium-dependent neutral amino acid transporter SLC6A17, sodium- and chloride-dependent transporter SLC6A20 for small amino acids including glycine and proline, GABA transporter-1 and 2 (GAT1; GAT2), and cationic amino acid transporter CAT2.
“Several AA transporters have been recently identified in pericytes, including the high-affinity excitatory AA transporter EAAT2 (28), sodium-dependent neutral AA transporter SLC6A17 (242), sodium- and chloride-dependent transporter SLC6A20 for small AA including glycine and proline (28, 129, 242), GABA transporter-1 and 2 (GAT1; GAT2) (28), and the cationic AA transporter CAT2 (28, 242).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
In Results, Table 4 lists Slc6a17 under category A, BBB-enriched endothelial transporters; its note explicitly says pericyte genes were excluded from that category. This contradicts the citation’s identification of SLC6A17 as a pericyte transporter. The passages found do not establish the claimed pericyte identification of SLC6A20 or CAT2. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPericytes, SMCs, and endothelial cells express thousands of transcripts encoding different transporters, receptors, active efflux pumps, ion channels, and regulatory molecules, whose expression pattern varies by zonation along the arteriocapillary-venous axis and cell type.
“Pericytes, SMCs, and endothelial cells express thousands of transcripts encoding different transporters, receptors, active efflux pumps, ion channels, and regulatory molecules (28, 72, 86, 129, 242, 358, 359, 610, 675, 678), whose expression pattern varies by zonation along the arteriocapillary-venous axis and cell type (610).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredOrganic anions are transported via the organic anion transporter OATP3A1 in pericytes.
“Organic anions are transported via the organic anion transporter OATP3A1 (28, 129, 242).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
Table 1B in Results > Purification of CNS Vascular Cells lists Slco3a1 among pericyte-enriched transcripts, supporting the pericyte association. Results > Elucidation of the Set of BBB-Enriched Transporters discusses transporter expression but says their substrates remain to be elucidated; it does not show that OATP3A1 transports organic anions in pericytes. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTranscriptomic studies suggest that pericytes express Na+-K+-ATPase α- and β-subunits, as well as Ca2+-ATPases.
“Transcriptomic studies suggest that pericytes express Na + -K + -ATPase 𝛂 - and 𝛃 -subunits (28, 129, 242), as well as Ca 2 + -ATPases (28, 129, 242).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
Table 1 in the Results section on CNS vascular-cell purification lists Atp1a2, a Na+-K+-ATPase α-subunit gene, among pericyte-enriched transcripts. The passages on pericyte-enriched transporters do not identify Na+-K+-ATPase β-subunits or Ca2+-ATPases, so those parts of the claim are not supported by our copy. No page numbers are available for these passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPericytes express the ATP-sensitive K+ channel ABCC9, the H+-peptide transporter SLC15A2, the Na+-I- symporter SLC5A5, and the inwardly rectifying potassium channel Kir6.1.
“Furthermore, pericytes express the ATP-sensitive K + channel ATP-binding cassette subfamily C member 9 (ABCC9), the H + -peptide transporter SLC15A2 (28), the Na + -I -symporter SLC5A5 (242), and inwardly rectifying potassium (KIR ) channel Kir6.1 (28, 72, 129, 242).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
In Results, Table 1 lists Abcc9 and Kcnj8 among the most enriched CNS pericyte transcripts, supporting the ABCC9 and Kir6.1 portions of the claim. Searches for Slc15a2 and Slc5a5 found no passage in our copy identifying either as expressed by pericytes. The claim’s inclusion of those two transporters is therefore not supported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Recent transcriptomic studies suggest that pericytes express multiple transporters, receptors, and ion channels.
“Recent transcriptomic studies suggest that pericytes express multiple transporters, receptors, and ion channels (28, 72, 129, 242, 675, 678).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
Pericytes express the vitamin transporter reduced folate carrier-1 (RFC1).
“Additionally, pericytes express the vitamin transporter reduced folate carrier-1 (RFC1) (28, 72, 129, 242, 675).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
Slc2a1 transcript encoding GLUT1 is one of the most abundant transcripts in brain endothelium.
“The importance of glucose transport across the BBB is best illustrated by the fact that Slc2a1 transcript encoding GLUT1 is one of the most abundant transcripts in brain endothelium (129).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
A complete transcriptome dataset that allows direct comparison of gene expression across all major glial and vascular brain cell types is lacking.
“a complete transcriptome dataset that allows direct comparison of gene expression across all of the major glial and vascular brain cell types is lacking.”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Daneman et al., 2010
The Results (Identification of the Blood-Brain Barrier Transcriptome; page unavailable) compare brain endothelial profiles with glial profiles from Cahoy et al., and the Discussion describes this paper’s vascular transcriptome resource. Neither section says that a complete dataset permitting direct comparison across all major glial and vascular brain cell types is lacking. Searches for that assertion and for the cell types did not find it in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredPericytes express lipoprotein receptor LRP1.
“Pericytes express lipoprotein receptor LRP1 (129, 513), which mediates cellular uptake of A 𝛃 followed by its intracellular degradation and clearance (513, 647).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [129]
The Results section discusses pericyte transcriptomes and names several pericyte-expressed receptors, but does not identify LRP1 among them. Searches for “Lrp1” and “low density lipoprotein receptor-related protein 1” found no passage establishing its expression in pericytes; the paper instead lists Lrp8 in its BBB-enriched transcript table (page unavailable). (LLM, conf=0.73)
Experimental — accuracy not yet measuredTfR is expressed at high levels at the blood-brain barrier due to its physiological function to deliver iron to the brain.
“As the TfR is expressed at high levels at the blood–brain barrier [106,107] due to its physiological function to deliver iron to the brain, it is one of the most studied molecules for receptor-mediated drug delivery to the brain.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [106]
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- Authors
- Daneman, R., Zhou, L., Agalliu, D., Cahoy, J. D., Kaushal, A., & Barres, B. A.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- Corresponding author
- Daneman, Richard
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-10-29
- Volume
- 5
- Issue
- 10
- Pages
- e13741
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2966423
- OpenAlex
- W2130962254
- Cited by
- 577
- References
- 57
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 27 · 2023: 41 · 2022: 47 · 2021: 47 · 2020: 62 · 2019: 50 · 2018: 46 · 2017: 54 · 2016: 26 · 2015: 42 · 2014: 36 · 2013: 23 · 2012: 22
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Multiple Sclerosis Society
- American Heart Association
- Myelin Repair Foundation
- Multiple Sclerosis Society
- National Institute of Neurological Disorders and Stroke (R01NS045621)
- 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 › Extracellular vesicles in disease
- Keywords
- blood-brain barrier, brain endothelial cells, transcriptome, mice, tight junction proteins, transporters, metabolic enzymes, signaling components, liver endothelial cells, pulmonary endothelial cells
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Cell Separation, Endothelium, Vascular, Flow Cytometry, In Situ Hybridization, Gene Expression Profiling, Mice
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