The Secreted Neuronal Signal Spock1 Promotes Blood-brain Barrier Development

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2023 Jul 12

PMID 37437574

Authors

Natasha M OBrown

Nikit B Patel

Ursula Hartmann

Allon M Klein

Chenghua Gu

Sean G Megason

Affiliations

Soon will be listed here.

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.

Citing Articles

The kinase RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during central nervous system viral infection.

Estevez I, Buckley B, Lindman M, Panzera N, Chou T, McCourt M Immunity. 2025; 58(3):666-682.e6.

PMID: 39999836 PMC: 11903149. DOI: 10.1016/j.immuni.2025.01.017.

Deciphering the Blood-Brain Barrier Paradox in Brain Metastasis Development and Therapy.

Peters J, Teng C, Peng K, Li X Cancers (Basel). 2025; 17(2).

PMID: 39858080 PMC: 11764143. DOI: 10.3390/cancers17020298.

Roles of SPOCK1 in the Formation Mechanisms and Treatment of Non-Small-Cell Lung Cancer and Brain Metastases from Lung Cancer.

Zhang X, Zhang X, Yin H, Li Q, Fan B, Jiang B Onco Targets Ther. 2025; 18():35-47.

PMID: 39835273 PMC: 11745074. DOI: 10.2147/OTT.S483576.

Zebrafish glial-vascular interactions progressively expand over the course of brain development.

Gall L, Stains C, Freitas-Andrade M, Jia B, Patel N, Megason S iScience. 2025; 28(1):111549.

PMID: 39811646 PMC: 11731618. DOI: 10.1016/j.isci.2024.111549.

Transcriptional Patterns in Stages of Alzheimer's Disease Are Cell-Type-Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans.

Joshi A, Giorgi F, Sanna P eNeuro. 2024; 11(10).

PMID: 39299805 PMC: 11485264. DOI: 10.1523/ENEURO.0118-24.2024.

References

Jeong J, Kwon H, Ahn J, Kang D, Kwon S, Park J . Functional and developmental analysis of the blood-brain barrier in zebrafish. Brain Res Bull. 2008; 75(5):619-28. DOI: 10.1016/j.brainresbull.2007.10.043. View

Vancza L, Tatrai P, Reszegi A, Baghy K, Kovalszky I . SPOCK1 with unexpected function. The start of a new career. Am J Physiol Cell Physiol. 2022; 322(4):C688-C693. DOI: 10.1152/ajpcell.00033.2022. View

Siegenthaler J, Choe Y, Patterson K, Hsieh I, Li D, Jaminet S . Foxc1 is required by pericytes during fetal brain angiogenesis. Biol Open. 2013; 2(7):647-59. PMC: 3711032. DOI: 10.1242/bio.20135009. View

Wolf F, Angerer P, Theis F . SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 2018; 19(1):15. PMC: 5802054. DOI: 10.1186/s13059-017-1382-0. View

Campbell M, Kiang A, Kenna P, Kerskens C, Blau C, ODwyer L . RNAi-mediated reversible opening of the blood-brain barrier. J Gene Med. 2008; 10(8):930-47. DOI: 10.1002/jgm.1211. View

Stewart P, Wiley M . Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail--chick transplantation chimeras. Dev Biol. 1981; 84(1):183-92. DOI: 10.1016/0012-1606(81)90382-1. View

Klein A, Mazutis L, Akartuna I, Tallapragada N, Veres A, Li V . Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell. 2015; 161(5):1187-1201. PMC: 4441768. DOI: 10.1016/j.cell.2015.04.044. View

Nakada M, Yamada A, Takino T, Miyamori H, Takahashi T, Yamashita J . Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes. Cancer Res. 2001; 61(24):8896-902. View

Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla C . Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol. 2008; 183(3):409-17. PMC: 2575783. DOI: 10.1083/jcb.200806024. View

10.

Du Z, Lin Z, Wang Z, Liu D, Tian D, Xia L . SPOCK1 overexpression induced by platelet-derived growth factor-BB promotes hepatic stellate cell activation and liver fibrosis through the integrin α5β1/PI3K/Akt signaling pathway. Lab Invest. 2020; 100(8):1042-1056. DOI: 10.1038/s41374-020-0425-4. View

11.

Ye Z, Chen J, Hu X, Yang S, Xuan Z, Lu X . SPOCK1: a multi-domain proteoglycan at the crossroads of extracellular matrix remodeling and cancer development. Am J Cancer Res. 2020; 10(10):3127-3137. PMC: 7642659. View

12.

Lyck R, Ruderisch N, Moll A, Steiner O, Cohen C, Engelhardt B . Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. J Cereb Blood Flow Metab. 2009; 29(9):1491-502. DOI: 10.1038/jcbfm.2009.72. View

13.

Harik S, Kalaria R, Andersson L, Lundahl P, Perry G . Immunocytochemical localization of the erythroid glucose transporter: abundance in tissues with barrier functions. J Neurosci. 1990; 10(12):3862-72. PMC: 6570044. View

14.

Blader P, Plessy C, Strahle U . Multiple regulatory elements with spatially and temporally distinct activities control neurogenin1 expression in primary neurons of the zebrafish embryo. Mech Dev. 2003; 120(2):211-8. DOI: 10.1016/s0925-4773(02)00413-6. View

15.

Derk J, Como C, Jones H, Joyce L, Kim S, Spencer B . Formation and function of the meningeal arachnoid barrier around the developing mouse brain. Dev Cell. 2023; 58(8):635-644.e4. PMC: 10231667. DOI: 10.1016/j.devcel.2023.03.005. View

16.

Ohlig S, Clavreul S, Thorwirth M, Simon-Ebert T, Bocchi R, Ulbricht S . Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4. EMBO J. 2021; 40(21):e107532. PMC: 8561644. DOI: 10.15252/embj.2020107532. View

17.

Choi H, Schwarzkopf M, Fornace M, Acharya A, Artavanis G, Stegmaier J . Third-generation hybridization chain reaction: multiplexed, quantitative, sensitive, versatile, robust. Development. 2018; 145(12). PMC: 6031405. DOI: 10.1242/dev.165753. View

18.

Schinkel . P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev. 2000; 36(2-3):179-194. DOI: 10.1016/s0169-409x(98)00085-4. View

19.

Janzer R, Raff M . Astrocytes induce blood-brain barrier properties in endothelial cells. Nature. 1987; 325(6101):253-7. DOI: 10.1038/325253a0. View

20.

Armulik A, Genove G, Mae M, Nisancioglu M, Wallgard E, Niaudet C . Pericytes regulate the blood-brain barrier. Nature. 2010; 468(7323):557-61. DOI: 10.1038/nature09522. View