PUBLICATION

The secreted neuronal signal spock1 promotes blood-brain barrier development

Authors
O'Brown, N.M., Patel, N.B., Hartmann, U., Klein, A.M., Gu, C., Megason, S.G.
ID
ZDB-PUB-230713-39
Date
2023
Source
Developmental Cell   58(17): 1534-1547.e6 (Journal)
Registered Authors
Megason, Sean, O'Brown, Natasha
Keywords
blood vessel, blood-brain barrier, development, genetics, leakage, zebrafish
Datasets
GEO:GSE230236
MeSH Terms
  • Animals
  • Biological Transport
  • Blood-Brain Barrier*/metabolism
  • Brain
  • Endothelium/metabolism
  • Mice
  • Proteoglycans*/metabolism
  • Zebrafish*
(all 8)
PubMed
37437574 Full text @ Dev. Cell
Abstract
The blood-brain barrier (BBB) is a unique set of properties of the brain vasculature which severely restrict its permeability to proteins and small molecules. Classic chick-quail chimera studies have shown that these properties are not intrinsic to the brain vasculature but rather are induced by surrounding neural tissue. Here, we identify Spock1 as a candidate neuronal signal for regulating BBB permeability in zebrafish and mice. Mosaic genetic analysis shows that neuronally expressed Spock1 is cell non-autonomously required for a functional BBB. Leakage in spock1 mutants is associated with altered extracellular matrix (ECM), increased endothelial transcytosis, and altered pericyte-endothelial interactions. Furthermore, a single dose of recombinant SPOCK1 partially restores BBB function in spock1 mutants by quenching gelatinase activity and restoring vascular expression of BBB genes including mcamb. These analyses support a model in which neuronally secreted Spock1 initiates BBB properties by altering the ECM, thereby regulating pericyte-endothelial interactions and downstream vascular gene expression.
Genes / Markers
Marker Marker Type Name
cldn5bGENEclaudin 5b
csf1raGENEcolony stimulating factor 1 receptor, a
dlbGENEdeltaB
elavl3GENEELAV like neuron-specific RNA binding protein 3
fabp4aGENEfatty acid binding protein 4a
foxc1bGENEforkhead box C1b
gad1bGENEglutamate decarboxylase 1b
gcGENEGC vitamin D binding protein
gstp1.1GENEglutathione S-transferase pi 1.1
kdrlGENEkinase insert domain receptor like
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Figures
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
spock1hm41/+; s896Tgstandard conditionsDay 5
spock1hm41/+; s896Tgstandard conditionsDay 5
spock1hm41/+; s896Tgstandard conditionsDay 5
spock1hm41/hm41standard conditionsDays 7-13
spock1hm41/hm41standard conditionsDays 7-13
spock1hm41/hm41; s896Tgstandard conditionsProtruding-mouth
spock1hm41/hm41; s896Tgstandard conditionsProtruding-mouth
spock1hm41/hm41; s896Tgstandard conditionsProtruding-mouth
spock1hm41/hm41; s896Tgstandard conditionsDay 5
spock1hm41/hm41; s896Tgstandard conditionsDay 5
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a13203TgTransgenic Insertion
    hm30TgTransgenic Insertion
      hm41
        		Complex
        hm43
          		Small Deletion
          hm44TgTransgenic Insertion
          lri500TgTransgenic Insertion
            ncv22TgTransgenic Insertion
              s896TgTransgenic Insertion
                sb2TgTransgenic Insertion
                  sj3TgTransgenic Insertion
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    csf1raCRISPR5-csf1raCRISPR
                    csf1raCRISPR6-csf1raCRISPR
                    csf1raCRISPR7-csf1raCRISPR
                    csf1raCRISPR8-csf1raCRISPR
                    gstp1.1CRISPR3-gstp1.1CRISPR
                    gstp1.1CRISPR1-gstp1.1CRISPR
                    gstp1.1CRISPR2-gstp1.1CRISPR
                    spock1CRISPR3-spock1CRISPR
                    spock1CRISPR4-spock1CRISPR
                    spock1CRISPR5-spock1CRISPR
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                    Fish
                    Fish
                    AB
                    lri500Tg; s896Tg
                    s896Tg
                    s896Tg; sj3Tg
                    sj3Tg
                    spock1hm41/hm41
                    spock1hm41/hm41; lri500Tg; s896Tg
                    spock1hm41/hm41; s896Tg
                    spock1hm41/+; s896Tg
                    spock1hm43/hm43; s896Tg; sj3Tg
                    1 - 10 of 14
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                    Antibodies
                    Orthology
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    CitrineEFGCitrine
                    EGFPEFGEGFP
                    GCaMPEFGGCaMP
                    GFPEFGGFP
                    mCherryEFGmCherry
                    1 - 5 of 5
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                    Mapping
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                    Citation
                    O'Brown, N.M., Patel, N.B., Hartmann, U., Klein, A.M., Gu, C., Megason, S.G. (2023) The secreted neuronal signal spock1 promotes blood-brain barrier development. Developmental Cell. 58(17):1534-1547.e6.