The secreted neuronal signal Spock1 promotes blood-brain barrier development.

Natasha M O'Brown, Nikit B Patel, Ursula Hartmann, Allon M Klein, Chenghua Gu, Sean G Megason

Developmental cell 2023 Sep 11

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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. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Natasha M O'Brown, Nikit B Patel, Ursula Hartmann, Allon M Klein, Chenghua Gu, Sean G Megason. The secreted neuronal signal Spock1 promotes blood-brain barrier development. Developmental cell. 2023 Sep 11;58(17):1534-1547.e6