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bioRxiv · 10.1101/2021.10.13.464312

The secreted neuronal signal Spock1 regulates the blood-brain barrier

O'Brown, N. M.·Patel, N. B.·Hartmann, U.·Klein, A. M.·Gu, C.·Megason, S. G.
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Abstract

The blood-brain barrier (BBB) is a unique set of properties of the brain vasculature which severely restricts its permeability to proteins and small molecules. Classic chick-quail chimera studies showed 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 induces BBB properties by altering the ECM, thereby regulating pericyte-endothelial interactions and downstream vascular gene expression. One-Sentence SummarySpock1 is a signal secreted by neurons that induces barrier properties in the brain vasculature

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O'Brown, N. M., Patel, N. B., Hartmann, U., Klein, A. M., Gu, C., Megason, S. G.. 2021-10-15. The secreted neuronal signal Spock1 regulates the blood-brain barrier. https://doi.org/10.1101/2021.10.13.464312

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