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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 5

GPR126 modulates LRP1 expression levels.

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GPR126 modulates LRP1 expression levels.
(A–C) RNA sequencing of fBECs f...
(A–C) RNA sequencing of fBECs from WT and Gpr126iECKO mice at P18. (A) Normalized enrichment scores from GSEA for differentially expressed genes in Gpr126iECKO (P ≤ 0.01, adjusted P ≤ 0.05, at least 30 altered genes). (B) Heatmap displaying z scores of leading-edge genes from GSEA for selected GO terms (n = 4 WT, n = 4 Gpr126iECKO mice per replicate). (C) Log2 fold change of selected genes differentially expressed in Gpr126iECKO. (D) Real-time qPCR of Lrp1 in fBECs (n = 7 WT, n = 9 Gpr126iECKO). (E and F) Immunoblotting for LRP1 in fBECs from WT and Gpr126iECKO mice at P18 (E) normalized over GAPDH (F) (n = 3 WT, n = 3 Gpr126iECKO). (G) FISH confocal images for Lrp1 (red) and Cldn5 (green) mRNA in cBECs from WT and Gpr126iECKO mice at P18. Scale bar: 20 μm. (H) Single-molecule RNA (smRNA) of Lrp1 per nucleus in G. Each symbol represents a field of 40 cells (n = 9 WT, n = 6 Gpr126iECKO). (I and J) Immunoblotting for LRP1 (I) normalized over vinculin (J) in cBECs transfected with control or Gpr126 siRNA and treated with collagen IV or PBS (I) (n = 6 WT mice). (K and L) Immunoblotting for total CREB and phospho-CREB S133 (K) normalized over vinculin (L) in cBECs treated as in I (n = 12 WT mice). (M–O) Immunoblotting for LRP1 and GPR126 in cBECs from adult WT and Lrp1iECKO (M), normalized over vinculin (N and O) (n = 3 WT, n = 3 Lrp1iECKO). (P) GPR126 regulates LRP1 expression and vice versa. 1. Collagen IV–GPR126 interactions induce cAMP, phospho-CREB, and LRP1. 2. LRP1 localizes at the plasma membrane. 3. This supports GPR126 expression and signaling. Dashed arrow, undefined LRP1-mediated induction of GPR126. Data are shown as means ± SD. (F, J, K, N, and O) Each symbol represents an experiment. (D, F, H, N, and O) Unpaired t tests with Welch’s correction; (J and L) Brown-Forsythe and Welch’s ANOVA, Dunnett’s T3 multiple-comparison tests. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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