mfsd2aa encodes one of the two zebrafish Mfsd2a paralogs, a multi-pass membrane protein of the major facilitator superfamily that works as a sodium-dependent lysophosphatidylcholine (LPC) symporter. It is expressed in brain microvascular endothelium, where it carries LPC species esterified to long-chain fatty acids, notably docosahexaenoic acid, from the luminal leaflet into the endothelial cell and on into the brain; it does not transport unesterified fatty acids. Through this lipid flux it shapes the lipid composition of barrier endothelium and suppresses vesicular transcytosis, so loss of mfsd2aa leaves tight junctions intact but raises endothelial vesicle density and makes the blood-brain barrier leaky in larvae and adults. The paralog mfsd2ab does not substitute for it in barrier function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0015245 fatty acid transmembrane transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: Fatty acid transmembrane transporter activity claims transfer of free fatty acids across a membrane. Mfsd2a transports the fatty acid only as the acyl chain of a lysophosphatidylcholine; UniProt states explicitly that it does not transport unesterified DHA, and the assayed ligands are LPC species [PMID:26005868]. Reason: The substrate of this transporter is a lysophospholipid, not a fatty acid, so the term names the wrong chemical species: DHA reaches the brain because it is esterified to LPC. The PAINT donors (mouse Mfsd2a, human MFSD2A) carry both this term and the LPC symporter term, so the node is about the right protein family but the fatty-acid term is the imprecise member of that pair. Replace with the lysophospholipid:sodium symporter term, which the gene already carries by IBA and ISS. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002602210 SUPPORTS SOURCE BUT NOT TARGET The node is the correct Mfsd2a family node, but the transported species at it is LPC; the free-fatty-acid term conflates the cargo with the acyl chain it carries, and it is contradicted for the orthologs by the explicit absence of unesterified DHA transport. Proposed replacements: lysophospholipid:sodium symporter activity Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Does not transport docosahexaenoic acid in unesterified fatty acid. file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A |
| GO:0055085 transmembrane transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Transmembrane transport is the generic parent process: solute moved across a bilayer. True of mfsd2aa, whose specific version (Na+-coupled LPC symport) is annotated separately. Reason: Correct but uninformative: it is an ancestor of the lysophospholipid transport terms that carry the real content, so it should not stand as a core function. Retained rather than removed because the IBA node (PTN000140373, the broad MFS node including bacterial permeases) is placed at a level where only this generic statement is safe. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Reaction=a 1-acyl-sn-glycero-3-phosphocholine(in) + Na(+)(in) |
| GO:0015908 fatty acid transport | IBA GO_REF:0000033 | MODIFY | Summary: Fatty acid transport asserts directed movement of fatty acids. What mfsd2aa moves is LPC carrying a long-chain acyl group; the free acid is not a substrate [file UniProt; PMID:26005868]. IBA from PTN002602210. Reason: Same scoping problem as the matching molecular-function row, and given the same action for consistency: the process the protein executes is lysophospholipid transport, with the fatty acid moving as a passenger on the LPC headgroup-bearing carrier. GO:0051977 lysophospholipid transport is already on the gene from ARBA and from the zebrafish IDA, and states the transported entity correctly. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002602210 SUPPORTS SOURCE BUT NOT TARGET Family node correct; the cargo term is not. Mouse and human orthologs move LPC-esterified, not free, fatty acids. Proposed replacements: lysophospholipid transport Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Does not transport docosahexaenoic acid in unesterified fatty acid. file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A |
| GO:0140329 lysophospholipid translocation | IBA GO_REF:0000033 | ACCEPT | Summary: Lysophospholipid translocation means moving a lysophospholipid from one bilayer leaflet to the other. Reconstituted Mfsd2a flips lysophosphatidylserine from the outer to the inner leaflet of liposomes in a sodium-dependent manner, establishing the family as a lysolipid flippase [PMID:36848557], consistent with the cryo-EM transport mechanism [PMID:34349262]. IBA from PTN002602210 (mouse Mfsd2a, human MFSD2A). Reason: The PAINT node placement is supported by direct biochemistry on the mammalian ortholog published after the node was made: flipping, not just translocation across the membrane, is the mechanism. The zebrafish protein transports the same LPC ligands with the same sodium dependence, so there is no reason to place the fish outside the clade that inherited this mechanism. Supporting Evidence: PMID:36848557 we demonstrate that Mfsd2a flips LPS from the outer to the inner leaflet of a membrane bilayer in a sodium-dependent manner PMID:36848557 These studies provide direct biochemical evidence that Mfsd2a functions as a lysolipid flippase. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A |
| GO:1990379 lipid transport across blood-brain barrier | IBA GO_REF:0000033 | ACCEPT | Summary: Lipid transport across the blood-brain barrier: the LPC flux that mfsd2aa catalyses is the route by which DHA-bearing lysolipid crosses barrier endothelium into the brain [file UniProt; PMID:34349262]. IBA from PTN002602210. Reason: This term states the gene product's own transport work placed in its anatomical context, so participation is direct rather than inferred from a phenotype. The zebrafish protein transports the same LPC ligands in a cell assay and is expressed in barrier endothelium, so the phylogenetic and ortholog transfers both land correctly. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A PMID:34349262 MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane, the site of the transport activity: Mfsd2a is a cell-surface multi-pass protein in brain microvascular endothelium, taking up LPC from the luminal side [file UniProt]. IBA from PTN000140373/PTN002602210 with mouse Mfsd2a among the donors. Reason: The location where the annotated activity occurs; in zebrafish the protein's barrier function requires it to act at the endothelial surface, and the TEM and tracer phenotypes of mfsd2aa mutants are endothelial [PMID:31429822]. No conflicting localisation data for the fish protein. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt SUBCELLULAR LOCATION: Cell membrane file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. PMID:31429822 mfsd2aa mutants have increased vesicular densities |
| GO:0051978 lysophospholipid:sodium symporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Lysophospholipid:sodium symporter activity, the direct molecular function. Zebrafish mfsd2aa expressed in HEK293 cells takes up LPC ligands at a level comparable to human MFSD2A [PMID:26005868], and the orthologous protein is a Na+-coupled LPC transporter with a defined sodium-binding site [PMID:34349262]. IBA from PTN002602210 (mouse Mfsd2a, human Q8NA29). Reason: This is the activity the zebrafish protein was directly assayed for: the transport assay in PMID:26005868 used the zebrafish mfsd2aa plasmid itself, so the propagation is corroborated by target-specific data rather than resting on the node alone. Sodium coupling and LPC selectivity are established for the orthologs, and UniProt writes the reaction as an Na+-coupled 1-acyl-sn-glycero-3-phosphocholine symport. Core function. Supporting Evidence: PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Reaction=a 1-acyl-sn-glycero-3-phosphocholine(in) + Na(+)(in) PMID:34349262 MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endoplasmic reticulum membrane, from the UniProt subcellular-location mapping; UniProt lists ER membrane alongside cell membrane for this protein, inferred by similarity from mouse Mfsd2a. Reason: Retained because it is a faithful transfer of the UniProt record, but marked non-core: the ER pool has no functional characterisation in zebrafish, and every phenotype and transport measurement for mfsd2aa concerns the plasma-membrane pool. Not enough to call this a site of the core activity. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Multi-pass membrane protein {ECO:0000255}. Endoplasmic reticulum membrane file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane, the site of the transport activity: Mfsd2a is a cell-surface multi-pass protein in brain microvascular endothelium, taking up LPC from the luminal side [file UniProt]. IEA from the UniProt subcellular-location mapping. Reason: The location where the annotated activity occurs; in zebrafish the protein's barrier function requires it to act at the endothelial surface, and the TEM and tracer phenotypes of mfsd2aa mutants are endothelial [PMID:31429822]. No conflicting localisation data for the fish protein. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt SUBCELLULAR LOCATION: Cell membrane file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. PMID:31429822 mfsd2aa mutants have increased vesicular densities |
| GO:0008643 carbohydrate transport | IEA GO_REF:0000002 | REMOVE | Summary: Carbohydrate transport, assigned by InterPro2GO from IPR039672 (Lactose permease-like), a family entry built around bacterial sodium:galactoside symporters. No sugar transport has been reported for any Mfsd2a protein; the characterised substrates are LPC species [PMID:26005868; PMID:34349262]. Reason: This is a demonstrably wrong electronic mapping, not an over-broad one: the signature groups Mfsd2a with lactose permease on fold similarity, and the GO mapping then transfers the bacterial family's sugar cargo. The protein transports lysophospholipids with sodium, and no assay of the mammalian or zebrafish protein has shown carbohydrate uptake, so the annotation asserts a substrate class the evidence does not support. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A |
| GO:0015293 symporter activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Symporter activity: coupled movement of two species in the same direction. Correct for mfsd2aa, which co-transports Na+ with LPC; the sodium-binding site is conserved and was mapped in the mouse structure [PMID:34349262]. Reason: Accurate but generic - it is the parent of GO:0051978, which names both the coupling ion and the substrate and is annotated from IBA, ISS and zebrafish transport data. Kept as supporting detail rather than as the core molecular function. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter PMID:34349262 MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Reaction=a 1-acyl-sn-glycero-3-phosphocholine(in) + Na(+)(in) |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Membrane, from the same InterPro family signature. The protein is indeed an integral multi-pass membrane protein, but its compartments are known: plasma membrane and endoplasmic reticulum membrane. Reason: Not wrong, just the uninformative ancestor of the two specific compartment terms the gene already carries from UniProt subcellular location and from ISS. Replacing it with those keeps the true content of the electronic assignment while removing a root-level cellular component annotation. Proposed replacements: plasma membrane endoplasmic reticulum membrane Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt SUBCELLULAR LOCATION: Cell membrane file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Multi-pass membrane protein {ECO:0000255}. Endoplasmic reticulum membrane |
| GO:0051977 lysophospholipid transport | IEA GO_REF:0000117 | ACCEPT | Summary: Lysophospholipid transport by ARBA rule from the Mfsd2a family signature; the same process is supported directly for zebrafish mfsd2aa by the LPC uptake assay [PMID:26005868]. Reason: The automatic assignment names exactly the substrate class that experiment supports for this protein, so the rule is right at this level of granularity. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A |
| GO:0051978 lysophospholipid:sodium symporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Lysophospholipid:sodium symporter activity, the direct molecular function. Zebrafish mfsd2aa expressed in HEK293 cells takes up LPC ligands at a level comparable to human MFSD2A [PMID:26005868], and the orthologous protein is a Na+-coupled LPC transporter with a defined sodium-binding site [PMID:34349262]. ISS from mouse Mfsd2a (Q9DA75). Reason: This is the activity the zebrafish protein was directly assayed for: the transport assay in PMID:26005868 used the zebrafish mfsd2aa plasmid itself, so the propagation is corroborated by target-specific data rather than resting on the node alone. Sodium coupling and LPC selectivity are established for the orthologs, and UniProt writes the reaction as an Na+-coupled 1-acyl-sn-glycero-3-phosphocholine symport. Core function. Supporting Evidence: PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Reaction=a 1-acyl-sn-glycero-3-phosphocholine(in) + Na(+)(in) PMID:34349262 MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain |
| GO:1905603 regulation of blood-brain barrier permeability | IMP PMID:31429822 Suppression of transcytosis regulates zebrafish blood-brain ... | ACCEPT | Summary: Regulation of blood-brain barrier permeability, IMP from the mfsd2aahm37 germline mutant: larvae show at least twofold more parenchymal leak of injected 1 kDa NHS tracer and of the endogenous 80 kDa DBP-EGFP serum protein at 5 dpf, and adults leak DBP-EGFP throughout the brain [PMID:31429822]. Reason: Stronger evidence than the morphant row and specific to this paralog: mfsd2ab mutants have wild-type permeability, and double mutants are no worse than mfsd2aa single mutants, so the effect is attributable to this gene product. The mutant raises permeability by a defined endothelial mechanism (increased vesicle density) rather than through general sickness, which is what makes this regulation rather than a secondary phenotype. Supporting Evidence: PMID:31429822 Mfsd2aa mutants displayed at least a two-fold increase in midbrain and hindbrain parenchymal tracer leakage PMID:31429822 mfsd2ab mutants displayed similarly low levels of parenchymal tracer intensity to wild-type controls at 5 dpf PMID:31429822 mfsd2aa mutants exhibited DBP-EGFP extravasation into the brain parenchyma |
| GO:0035633 maintenance of blood-brain barrier | IMP PMID:26005868 Inactivating mutations in MFSD2A, required for omega-3 fatty... | ACCEPT | Summary: Maintenance of the blood-brain barrier, IMP from mfsd2aa morphants: 10 kDa and 2000 kDa dextran leaked from cranial vessels into brain parenchyma, and co-injected zebrafish or human wild-type MFSD2A mRNA rescued the leak while patient missense variants did not [PMID:26005868]. Reason: The morphant caveat the authors themselves raise is answered by the later germline mutants, which show the same barrier leak [PMID:31429822], and the rescue by wild-type but not transport-dead human MFSD2A ties the barrier defect to the protein's transport activity. Participation is satisfied: the lipid flux mfsd2aa carries out is itself the mechanism that keeps endothelial transcytosis suppressed, so this is work the gene product does, not a distal consequence. Supporting Evidence: PMID:26005868 dextran extravasated extensively from vessels as evidenced by fluorescence within the brain parenchyma of mfsd2aa morphant brains PMID:26005868 co-injection with either zebrafish and human mRNA largely rescued dextran extravasation PMID:31429822 Mfsd2aa mutants displayed at least a two-fold increase in midbrain and hindbrain parenchymal tracer leakage |
| GO:0051977 lysophospholipid transport | IDA PMID:26005868 Inactivating mutations in MFSD2A, required for omega-3 fatty... | ACCEPT | Summary: Lysophospholipid transport, IDA from the HEK293 uptake assay in which the zebrafish mfsd2aa construct transported radiolabelled LPC ligands as efficiently as human MFSD2A [PMID:26005868]. Reason: Direct assay of this gene product's own transport activity on the correct substrate class; this is the process the protein executes, not a downstream consequence. It is also the process term that the misdirected fatty-acid rows should collapse into. Supporting Evidence: PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma membrane, the site of the transport activity: Mfsd2a is a cell-surface multi-pass protein in brain microvascular endothelium, taking up LPC from the luminal side [file UniProt]. ISS from mouse Mfsd2a (Q9DA75). Reason: The location where the annotated activity occurs; in zebrafish the protein's barrier function requires it to act at the endothelial surface, and the TEM and tracer phenotypes of mfsd2aa mutants are endothelial [PMID:31429822]. No conflicting localisation data for the fish protein. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt SUBCELLULAR LOCATION: Cell membrane file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. PMID:31429822 mfsd2aa mutants have increased vesicular densities |
| GO:0015293 symporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Symporter activity: coupled movement of two species in the same direction. Correct for mfsd2aa, which co-transports Na+ with LPC; the sodium-binding site is conserved and was mapped in the mouse structure [PMID:34349262]. Reason: Accurate but generic - it is the parent of GO:0051978, which names both the coupling ion and the substrate and is annotated from IBA, ISS and zebrafish transport data. Kept as supporting detail rather than as the core molecular function. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Sodium-dependent lysophosphatidylcholine (LPC) symporter PMID:34349262 MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Reaction=a 1-acyl-sn-glycero-3-phosphocholine(in) + Na(+)(in) |
| GO:0015908 fatty acid transport | ISS GO_REF:0000024 | MODIFY | Summary: Fatty acid transport asserts directed movement of fatty acids. What mfsd2aa moves is LPC carrying a long-chain acyl group; the free acid is not a substrate [file UniProt; PMID:26005868]. ISS from mouse Mfsd2a (Q9DA75). Reason: Same scoping problem as the matching molecular-function row, and given the same action for consistency: the process the protein executes is lysophospholipid transport, with the fatty acid moving as a passenger on the LPC headgroup-bearing carrier. GO:0051977 lysophospholipid transport is already on the gene from ARBA and from the zebrafish IDA, and states the transported entity correctly. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q9DA75 SUPPORTS SOURCE BUT NOT TARGET Mouse Mfsd2a is the donor and is a genuine ortholog, but its own fatty-acid-transport annotation shares the imprecision: the assayed substrates are LPC species and unesterified DHA is explicitly not transported. Proposed replacements: lysophospholipid transport Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Does not transport docosahexaenoic acid in unesterified fatty acid. file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A |
| GO:0045056 transcytosis | ISS GO_REF:0000024 | MODIFY | Summary: Transcytosis (ISS from mouse Mfsd2a) asserts that the protein moves endocytosed material through the cell. Mfsd2a does the opposite: it suppresses vesicular transcytosis in barrier endothelium, and zebrafish mfsd2aa mutants show increased luminal and abluminal vesicle densities with intact tight junctions [PMID:31429822]. Reason: The direction of the relationship is inverted by this term. The protein is not a cargo carrier in the transcytotic route; its lipid transport changes the endothelial membrane so that caveolar vesicle formation is held down, and removing it releases that suppression. GO:1904299 negative regulation of transcytosis states what the loss-of-function data actually show, and the zebrafish mutant supplies direct evidence for it. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: UniProtKB:Q9DA75 SUPPORTS SOURCE BUT NOT TARGET Mouse Mfsd2a is the correct ortholog and is genuinely tied to transcytosis, but as its suppressor; transferring the bare process term makes the protein a participant in the route it inhibits. Proposed replacements: negative regulation of transcytosis Supporting Evidence: PMID:31429822 Mfsd2aa mutants exhibit increased transcytosis. PMID:31429822 mfsd2aa mutants have increased vesicular densities PMID:31429822 mfsd2ab mutants displayed similarly low levels of parenchymal tracer intensity to wild-type controls at 5 dpf |
| GO:0060856 establishment of blood-brain barrier | ISS GO_REF:0000024 | ACCEPT | Summary: Establishment of the blood-brain barrier, ISS from mouse Mfsd2a. The zebrafish gene is independently implicated: mfsd2aa vascular expression rises at 5 dpf when barrier endothelium suppresses transcytosis, and mutants fail to acquire a tight barrier at that stage [PMID:31429822]. Reason: The ISS transfer lands on a process the fish gene is directly shown to participate in, by a paralog-resolved germline mutant, so it is not a bare similarity claim. Timing supports establishment specifically rather than only maintenance: expression appears as the barrier matures. Supporting Evidence: PMID:31429822 Mfsd2aa mutants displayed at least a two-fold increase in midbrain and hindbrain parenchymal tracer leakage file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt which plays an essential role for blood-brain barrier formation and function. PMID:31429822 mfsd2ab mutants displayed similarly low levels of parenchymal tracer intensity to wild-type controls at 5 dpf |
| GO:1990379 lipid transport across blood-brain barrier | ISS GO_REF:0000024 | ACCEPT | Summary: Lipid transport across the blood-brain barrier: the LPC flux that mfsd2aa catalyses is the route by which DHA-bearing lysolipid crosses barrier endothelium into the brain [file UniProt; PMID:34349262]. ISS from mouse Mfsd2a (Q9DA75). Reason: This term states the gene product's own transport work placed in its anatomical context, so participation is direct rather than inferred from a phenotype. The zebrafish protein transports the same LPC ligands in a cell assay and is expressed in barrier endothelium, so the phylogenetic and ortholog transfers both land correctly. Supporting Evidence: file:DANRE/mfsd2aa/mfsd2aa-uniprot.txt Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. PMID:26005868 both mfsd2aa and mfsd2ab exhibit similar transport activity of LPC ligands, and to a similar level as human MFSD2A PMID:34349262 MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain |
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Download this section (compressed HTML)Q: Do the two zebrafish paralogs differ in substrate preference or only in vascular expression timing, given that mfsd2ab transports LPC in vitro yet its mutants have a normal barrier?
Q: Is the endoplasmic reticulum pool of Mfsd2aa functional in zebrafish, or is the ER localisation in UniProt an ortholog-derived inference without a role in the fish?
Experiment: Quantify brain lysophospholipid and DHA species by lipidomics in mfsd2aa, mfsd2ab and double mutant larvae and adults, alongside tracer permeability, to test whether barrier phenotype tracks brain LPC-DHA content.
Hypothesis: mfsd2aa, but not mfsd2ab, supplies DHA-LPC to the brain in vivo.
Type: lipidomics
Experiment: Rescue mfsd2aa mutants with transport-dead variants (equivalent to human p.Thr159Met/p.Ser166Leu) and score endothelial vesicle density by TEM and tracer leakage, separating the transport function from any structural role.
Hypothesis: Barrier tightening requires the transport activity itself rather than the presence of the protein.
Type: genetic rescue
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