Samarelli Anna Valeria, Riccitelli Elena, Bizzozero Laura, Silveira Tatiana Nunes, Seano Giorgio, Pergolizzi Margherita, Vitagliano Grazia, Cascone Ilaria, Carpentier Gilles, Bottos Alessia, Primo Luca, Bussolino Federico, Arese Marco
From the Department of Oncology, University of Torino Medical School, Laboratory of Neurovascular Biology.
From the Department of Oncology, University of Torino Medical School, Cell Migration.
J Biol Chem. 2014 Jul 11;289(28):19466-76. doi: 10.1074/jbc.M113.530972. Epub 2014 May 23.
The synaptic protein Neuroligin 1 (NLGN1), a cell adhesion molecule, is critical for the formation and consolidation of synaptic connectivity and is involved in vascular development. The mechanism through which NLGN1 acts, especially in vascular cells, is unknown. Here, we aimed at deepening our knowledge on the cellular activities and molecular pathways exploited by endothelial NLGN1 both in vitro and in vivo. We analyzed the phenotypic consequences of NLGN1 expression modulation in endothelial cells through in vitro angiogenesis assays and the mouse postnatal retinal angiogenesis model. We demonstrate that NLGN1, whereas not affecting endothelial cell proliferation or migration, modulates cell adhesion to the vessel stabilizing protein laminin through cooperation with the α6 integrin, a specific laminin receptor. Finally, we show that in vivo, NLGN1 and α6 integrin preferentially colocalize in the mature retinal vessels, whereas NLGN1 deletion causes an aberrant VE-cadherin, laminin and α6 integrin distribution in vessels, along with significant structural defects in the vascular tree.
突触蛋白神经连接蛋白1（NLGN1）是一种细胞粘附分子，对突触连接的形成和巩固至关重要，并参与血管发育。NLGN1发挥作用的机制，尤其是在血管细胞中的机制尚不清楚。在这里，我们旨在加深对内皮细胞NLGN1在体外和体内所利用的细胞活动和分子途径的了解。我们通过体外血管生成试验和小鼠出生后视网膜血管生成模型分析了内皮细胞中NLGN1表达调节的表型后果。我们证明，NLGN1虽然不影响内皮细胞的增殖或迁移，但通过与特定的层粘连蛋白受体α6整合素合作，调节细胞与血管稳定蛋白层粘连蛋白的粘附。最后，我们表明在体内，NLGN1和α6整合素优先共定位于成熟的视网膜血管中，而NLGN1的缺失会导致血管中VE-钙粘蛋白、层粘连蛋白和α6整合素的异常分布，以及血管树的明显结构缺陷。
