The ubiquitin ligase PDZRN3 is required for vascular morphogenesis through Wnt/planar cell polarity signalling

Raj N. Sewduth, Béatrice Jaspard-Vinassa, Claire Peghaire, Aude Guillabert, Nathalie Franzl, Frederic Larrieu-Lahargue, Catherine Moreau, Marcus Fruttiger, Pascale Dufourcq, Thierry Couffinhal and Cécile Duplàa ()
Additional contact information
Raj N. Sewduth: INSERM, Adaptation cardiovasculaire à l'ischémie
Béatrice Jaspard-Vinassa: INSERM, Adaptation cardiovasculaire à l'ischémie
Claire Peghaire: INSERM, Adaptation cardiovasculaire à l'ischémie
Aude Guillabert: INSERM, Adaptation cardiovasculaire à l'ischémie
Nathalie Franzl: INSERM, Adaptation cardiovasculaire à l'ischémie
Frederic Larrieu-Lahargue: INSERM, Adaptation cardiovasculaire à l'ischémie
Catherine Moreau: INSERM, Adaptation cardiovasculaire à l'ischémie
Marcus Fruttiger: UCL Institute of Ophthalmology
Pascale Dufourcq: INSERM, Adaptation cardiovasculaire à l'ischémie
Thierry Couffinhal: INSERM, Adaptation cardiovasculaire à l'ischémie
Cécile Duplàa: INSERM, Adaptation cardiovasculaire à l'ischémie

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Development and stabilization of a vascular plexus requires the coordination of multiple signalling processes. Wnt planar cell polarity (PCP) signalling is critical in vertebrates for diverse morphogenesis events, which coordinate cell orientation within a tissue-specific plane. However, its functional role in vascular morphogenesis is not well understood. Here we identify PDZRN3, an ubiquitin ligase, and report that Pdzrn3 deficiency impairs embryonic angiogenic remodelling and postnatal retinal vascular patterning, with a loss of two-dimensional polarized orientation of the intermediate retinal plexus. Using in vitro and ex vivo Pdzrn3 loss-of-function and gain-of-function experiments, we demonstrate a key role of PDZRN3 in endothelial cell directional and coordinated extension. PDZRN3 ubiquitinates Dishevelled 3 (Dvl3), to promote endocytosis of the Frizzled/Dvl3 complex, for PCP signal transduction. These results highlight the role of PDZRN3 to direct Wnt PCP signalling, and broadly implicate this pathway in the planar orientation and highly branched organization of vascular plexuses.

Date: 2014
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DOI: 10.1038/ncomms5832

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