The alternative splicing factor Nova2 regulates vascular development and lumen formation.

Costanza Giampietro, Gianluca Deflorian, Stefania Gallo, Anna Di Matteo, Davide Pradella, Serena Bonomi, Elisa Belloni, Daniel Nyqvist, Valeria Quaranta, Stefano Confalonieri, Giovanni Bertalot, Fabrizio Orsenigo, Federica Pisati, Elisabetta Ferrero, Giuseppe Biamonti, Evelien Fredrickx, Carla Taveggia, Chris D R Wyatt, Manuel Irimia, Pier Paolo Di Fiore, Benjamin J Blencowe, Elisabetta Dejana, Claudia Ghigna

Index: Nat. Commun. 6 , 8479, (2015)

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Abstract

Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.