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Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis

Abstract

Neurons have an important role in retinal vascular development. Here we show that the G protein–coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets.

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Figure 1: F2rl1 in retinal neurons promotes angiogenesis.
Figure 2: Translocation of F2rl1 from the plasma membrane to the cell nucleus.
Figure 3: Transport of F2RL1 by importin-β1 and SNX11.
Figure 4: Transcriptional activity of F2rl1 at the nucleus.
Figure 5: Subcellular location governs gene induction by F2rl1.
Figure 6: Nuclear F2rl1 contributes to retinal neovascularization.

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Acknowledgements

This study was supported by grants from the Canadian Institutes of Health Research (CIHR; P.S., F.G. Jr., C. Beauséjour, M.H., A.R.-d.-S., G.A. and S.C.), the March of Dimes Birth Defects Foundation (S.C.), the Foundation Fighting Blindness (J.-S.J. and P.S.), Fonds de la Recherche en Santé du Québec (J.-S.J., P.S., G.A. and S.C.), Le Réseau de Recherche en Santé de la Vision (P.S. and S.C.), the National Eye Institute (W.K.) and the Robert Welch Foundation (W.K.). J.-S.J. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the Canadian Child Health Clinician Scientist Program (CIHR). G.A. is a recipient of a CIHR Clinician-Scientist Scholarship. P.S. and S.C. hold Canada Research Chairs. S.C. holds the Leopoldine Wolfe Chair in translational research in age-related macular degeneration. We thank G. Bourque and L. Létourneau (Genome Quebec Innovation Center, McGill University) for advice on ChIP-Seq analysis, C. Brown (Life Sciences Imaging Facility, McGill University) for live imaging advice, D. Barbaz (Department of Pharmacology, Sherbrooke University) for support with scanning EM and M. Chai-An (Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center) for breeding Pou4f2LacZ-DTA/+ mice. We thank N. Agarwal (National Eye Institute, US National Institutes of Health) for providing RGC-5 cells and N. Bunnett (Department of Physiology, University of California) for providing F2RL1-GFP and Flag-F2RL1-HA plasmids.

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J.-S.J., S.N., T.Z., N.S. and S.C. conceived and designed the experiments. J.-S.J., S.N., T.Z., N.S., J.C.R., Z.S., P.S., D.H., M.S., K.Z., J.O., M.M.-Z., A.Z., E.P., V.B., F.G. Jr., C. Beauséjour, A.R.-d.-S., J.O. and M.S.-L. performed experiments. P.S., P.H., D.R.V., F.G., M.H., A.R.-d.-S. and G.A. provided expert advice. C. Boileau provided F2rl1−/− mice. W.K. provided Pou4f2LacZ-DTA/+ mice. G.A. and C. Beauséjour provided gene expression vectors. All authors analyzed the data. J.-S.J. and S.C. wrote the paper.

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Correspondence to Jean-Sébastien Joyal, Gregor Andelfinger or Sylvain Chemtob.

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Joyal, JS., Nim, S., Zhu, T. et al. Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis. Nat Med 20, 1165–1173 (2014). https://doi.org/10.1038/nm.3669

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