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GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system
Nikolaos Kakogiannos, … , Donato Inverso, Monica Giannotta
Nikolaos Kakogiannos, … , Donato Inverso, Monica Giannotta
Published August 1, 2024
Citation Information: J Clin Invest. 2024;134(15):e165368. https://doi.org/10.1172/JCI165368.
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Research Article Angiogenesis Vascular biology Article has an altmetric score of 5

GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system

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Abstract

The blood-brain barrier (BBB) acquires unique properties to regulate neuronal function during development. The formation of the BBB, which occurs in tandem with angiogenesis, is directed by the Wnt/β-catenin signaling pathway. Yet the exact molecular interplay remains elusive. Our study reveals the G protein–coupled receptor GPR126 as a critical target of canonical Wnt signaling, essential for the development of the BBB’s distinctive vascular characteristics and its functional integrity. Endothelial cell–specific deletion of the Gpr126 gene in mice induced aberrant vascular morphogenesis, resulting in disrupted BBB organization. Simultaneously, heightened transcytosis in vitro compromised barrier integrity, resulting in enhanced vascular permeability. Mechanistically, GPR126 enhanced endothelial cell migration, pivotal for angiogenesis, acting through an interaction between LRP1 and β1 integrin, thereby balancing the levels of β1 integrin activation and recycling. Overall, we identified GPR126 as a specifier of an organotypic vascular structure, which sustained angiogenesis and guaranteed the acquisition of the BBB properties during development.

Authors

Nikolaos Kakogiannos, Anna Agata Scalise, Emanuele Martini, Claudio Maderna, Andrea Francesco Benvenuto, Michele D’Antonio, Laura Carmignani, Serena Magni, Giorgia Serena Gullotta, Maria Grazia Lampugnani, Fabio Iannelli, Galina V. Beznoussenko, Alexander A. Mironov, Camilla Cerutti, Katie Bentley, Andrew Philippides, Federica Zanardi, Marco Bacigaluppi, Sara Sigismund, Claudia Bassani, Cinthia Farina, Gianvito Martino, Marco De Giovanni, Elisabetta Dejana, Matteo Iannacone, Donato Inverso, Monica Giannotta

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Figure 1

GPR126 is a target of Wnt/β-catenin signaling and is expressed in brain vasculature during BBB development.

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GPR126 is a target of Wnt/β-catenin signaling and is expressed in brain ...
(A) Volcano plot showing transcriptional changes in cBECs exposed to Wnt3a-conditioned medium versus control for 5 days. Genes with significant alterations (P < 0.05) are depicted (Fisher’s least significant difference test). Red dots, upregulated gene targets of Wnt/β-catenin; blue dots, downregulated genes. Gpr126 is highlighted in green. (B) Real-time qPCR of Axin2 and Gpr126 expression in cBECs and cLECs from adult WT mice treated with recombinant Wnt3a or control. (C) Real-time qPCR of Axin2 and Gpr126 in fBECs from mice at P18 (n = 6 WT, n = 9 dnTCF4iECKI mice). (D) Real-time qPCR of Axin2 and Gpr126 in iBECs with or without primary neonatal astrocytes and treated with vehicle or Wnt-C59 (n = 3). (E) Real-time qPCR of Gpr126 expression in fBECs from WT mice during embryonic (E11–E16) and postnatal (P2–P30) stages and in the adult (P90) (n = 8 embryos, n = 5 postnatal, n = 3 adults). (F and G) Immunoblotting for GPR126 in fBECs from different postnatal stages and adulthood (P8–P30 and P90), quantified by GPR126/VE-cadherin ratios (n = 3 WT mice). (H and I) FISH confocal imaging for Gpr126 (red) and Cldn5 (green) mRNA in mouse cortex at P18, quantified by Gpr126 single-molecule RNA (smRNA) per vessel area (number of spots/μm2). Each symbol represents a field (3–4 fields per region, n = 4 WT mice). C, cortex; S, striatum; V, ventricle; H, hippocampus. (J) Electron microscopy of GPR126 immunogold-labeled (10 nm) cryosection of brain capillaries from WT mouse cortex at P18. Top: Luminal plasma membrane (PM). Bottom: Abluminal EC and pericyte plasma membrane (PM). Right: Late endosome (LE). L, lumen. Scale bars: 200 nm. Data are shown as means ± SD. (B and D–G) Each symbol represents an experiment; Brown-Forsythe and Welch’s ANOVA, Dunnett’s T3 multiple-comparison tests. (B and C) Unpaired t tests with Welch’s correction. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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