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.

GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system / N. Kakogiannos, A.A. Scalise, E. Martini, C. Maderna, A.F. Benvenuto, M. D'Antonio, L. Carmignani, S. Magni, G.S. Gullotta, M.G. Lampugnani, F. Iannelli, G.V. Beznoussenko, A.A. Mironov, C. Cerutti, K. Bentley, A. Philippides, F. Zanardi, M. Bacigaluppi, S. Sigismund, C. Bassani, C. Farina, G. Martino, M. De Giovanni, E. Dejana, M. Iannacone, D. Inverso, M. Giannotta. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 134:15(2024 Aug 01), pp. e165368.1-e165368.18. [10.1172/jci165368]

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

E. Martini;A.F. Benvenuto;G.S. Gullotta;F. Iannelli;F. Zanardi;S. Sigismund;E. Dejana;
2024

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.
Settore BIOS-10/A - Biologia cellulare e applicata
   The role of GPCRs and homing molecules in the control and regionalization of mucosal immunity.
   GREMLIN
   European Commission
   Horizon Europe Framework Programme
   101116224

   Functional Biology of Hepatic CD8+ T cells
   FATE
   European Commission
   Horizon 2020 Framework Programme
   725038

   TOLERABILIDADE E INCOMENSURABILIDADE
   SFRH/BD/27564/2006
   Fundação para a Ciência e a Tecnologia, I.P.
   FARH
   SFRH/BD/27564/2006

   Inherited disfunctions of brain microcirculation
   V-EPC
   European Commission
   Horizon 2020 Framework Programme
   742922

   Mechanisms underlying dysfunctional CD8+ T cell responses in chronic hepatitis B
   MINISTERO DELL'UNIVERSITA' E DELLA RICERCA
   2022FMESXL_003
1-ago-2024
https://www.jci.org/articles/view/165368
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1133676
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