MPDZ promotes DLL4-induced Notch signaling during angiogenesis.

Fabian Tetzlaff,Anja Feldner,Andreas Fischer,Amitai Menuchin,M Gordian Adam,David Sprinzak,Iris Moll,Juan Rodriguez-Vita

doi:10.7554/elife.32860

Abstract

Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by influencing the cellular localization of Notch ligands. Here, we show that the multiple PDZ domain protein (MPDZ) enhances Notch signaling activity. MPDZ physically interacts with the intracellular carboxyterminus of DLL1 and DLL4 and enables their interaction with the adherens junction protein Nectin-2. Inactivation of the MPDZ gene leads to impaired Notch signaling activity and increased blood vessel sprouting in cellular models and the embryonic mouse hindbrain. Tumor angiogenesis was enhanced upon endothelial-specific inactivation of MPDZ leading to an excessively branched and poorly functional vessel network resulting in tumor hypoxia. As such, we identified MPDZ as a novel modulator of Notch signaling by controlling ligand recruitment to adherens junctions.

Highlights

Angiogenesis, the process of forming new blood vessels from pre-existing ones is essential for embryonic development, tissue growth, wound healing, and regeneration
multiple PDZ domain protein (MPDZ) physically interacts with the Notch ligands DLL1 and Delta-like ligand 4 (DLL4) and promotes Notch signaling
MPDZ has been identified in screening approaches as a putative binding partner of the Notch ligands DLL1 and DLL4 (Adam et al, 2013; Estrach et al, 2007; Wright et al, 2004)

Summary

Introduction

Angiogenesis, the process of forming new blood vessels from pre-existing ones is essential for embryonic development, tissue growth, wound healing, and regeneration. During a process called Notch signaling, the ligands bind to the receptor, which becomes active and helps to control angiogenesis It hinders excessive vessel branching and so prevents the blood vessels from becoming leaky and inefficient. When mice without MPDZ were transplanted with tumor cells, the tumors contained more, but leakier, blood vessels and were not supplied with enough oxygen This suggests that MPDZ is an important factor that helps to regulate angiogenesis by enhancing Notch signaling between tip and branch cells in a new blood vessel. As Notch receptor expression is often enriched at cellular junctions (Batchuluun et al, 2017; Benhra et al, 2011; Hatakeyama et al, 2014; Sasaki et al, 2007), we analyzed how the protein interaction of MPDZ with the Notch ligands DLL1 and DLL4 affects Notch signaling during angiogenesis

Results

Discussion

Materials and methods

Funding Funder