{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T23:55:00Z","timestamp":1787961300826,"version":"build-2784847793"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100017540","name":"NHLBI Division of Intramural Research","doi-asserted-by":"publisher","award":["1R01HLI125811"],"award-info":[{"award-number":["1R01HLI125811"]}],"id":[{"id":"10.13039\/100017540","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Research Council","award":["834161"],"award-info":[{"award-number":["834161"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["830299"],"award-info":[{"award-number":["830299"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell. Mol. Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The blood-retina barrier (BRB) protects retinal neuronal function and enables vision. A compromised, leaky BRB is a hallmark of vision-threatening retinal diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) that affect millions of persons worldwide. Strategies to enhance BRB integrity hold promise as therapeutic interventions to prevent vision loss. Previous studies identified Netrin-1 (\n                    <jats:italic>NTN1<\/jats:italic>\n                    ) as a key regulator of BRB stability and revealed reduced Netrin-1 signaling in DR patients, suggesting that Netrin-1 supplementation could help preserve BRB function and prevent disease progression. Herein, we used inducible genetic\n                    <jats:italic>NTN1<\/jats:italic>\n                    overexpression to investigate effects on BRB development and maintenance. We show that global\n                    <jats:italic>NTN1<\/jats:italic>\n                    overexpression converted leaky vessels at the P5 angiogenic front into a non-leaky state. In pathological settings,\n                    <jats:italic>NTN1<\/jats:italic>\n                    overexpression reinforced BRB integrity in oxygen-induced retinopathy (OIR), improving electroretinogram (ERG) amplitudes and rescued vascular leak in laser-induced choroidal neovascularization (CNV).\n                    <jats:italic>NTN1<\/jats:italic>\n                    overexpression or\n                    <jats:italic>Ntn1<\/jats:italic>\n                    knockout minimally and transiently affected retinal angiogenesis. Global\n                    <jats:italic>Unc5b<\/jats:italic>\n                    deletion phenocopied vascular leak observed in\n                    <jats:italic>Ntn1<\/jats:italic>\n                    deficient retinas, while angiogenesis defects differed between\n                    <jats:italic>Ntn1<\/jats:italic>\n                    and\n                    <jats:italic>Unc5b<\/jats:italic>\n                    knockouts. These findings establish Netrin-1 as a promising therapeutic target for preventing BRB breakdown in retinal vascular diseases and suggest that reinforcing the Netrin-1\/Unc5b signaling pathway may provide a strategy to selectively stabilize the BRB.\n                  <\/jats:p>","DOI":"10.1007\/s00018-025-05903-6","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T13:57:51Z","timestamp":1762437471000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Restoring compromised blood-retina-barrier integrity with Netrin-1 overexpression"],"prefix":"10.1007","volume":"82","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-2592","authenticated-orcid":false,"given":"Jessica","family":"Furtado","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Zapadka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Boy\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B.","family":"Demb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5563-210X","authenticated-orcid":false,"given":"Anne","family":"Eichmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"5903_CR1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41574-020-00451-4","volume":"17","author":"DA Antonetti","year":"2021","unstructured":"Antonetti DA, Silva PS, Stitt AW (2021) Current understanding of the molecular and cellular pathology of diabetic retinopathy. Nat Rev Endocrinol 17:195\u2013206. https:\/\/doi.org\/10.1038\/s41574-020-00451-4","journal-title":"Nat Rev Endocrinol"},{"key":"5903_CR2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.preteyeres.2013.02.001","volume":"34","author":"I Klaassen","year":"2013","unstructured":"Klaassen I, Van Noorden CJ, Schlingemann RO (2013) Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res 34:19\u201348. https:\/\/doi.org\/10.1016\/j.preteyeres.2013.02.001","journal-title":"Prog Retin Eye Res"},{"key":"5903_CR3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190062","author":"CP Profaci","year":"2020","unstructured":"Profaci CP, Munji RN, Pulido RS, Daneman R (2020) The blood-brain barrier in health and disease: important unanswered questions. J Exp Med. https:\/\/doi.org\/10.1084\/jem.20190062","journal-title":"J Exp Med"},{"key":"5903_CR4","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1152\/physrev.00050.2017","volume":"99","author":"MD Sweeney","year":"2019","unstructured":"Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99:21\u201378. https:\/\/doi.org\/10.1152\/physrev.00050.2017","journal-title":"Physiol Rev"},{"key":"5903_CR5","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.neuron.2014.03.003","volume":"82","author":"D Knowland","year":"2014","unstructured":"Knowland D et al (2014) Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82:603\u2013617. https:\/\/doi.org\/10.1016\/j.neuron.2014.03.003","journal-title":"Neuron"},{"key":"5903_CR6","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41591-018-0297-y","volume":"25","author":"DA Nation","year":"2019","unstructured":"Nation DA et al (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25:270\u2013276. https:\/\/doi.org\/10.1038\/s41591-018-0297-y","journal-title":"Nat Med"},{"key":"5903_CR7","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","volume":"37","author":"NJ Abbott","year":"2010","unstructured":"Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13\u201325. https:\/\/doi.org\/10.1016\/j.nbd.2009.07.030","journal-title":"Neurobiol Dis"},{"key":"5903_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2025.01.022","author":"BL VanderBeek","year":"2025","unstructured":"VanderBeek BL, Yu Y, Cardillo S, Hubbard R (2025) Twenty-year trends in prevalence and incidence of diabetic retinal disease. Ophthalmology. https:\/\/doi.org\/10.1016\/j.ophtha.2025.01.022","journal-title":"Ophthalmology"},{"key":"5903_CR9","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.cell.2014.09.025","volume":"159","author":"K Okabe","year":"2014","unstructured":"Okabe K et al (2014) Neurons limit angiogenesis by titrating VEGF in retina. Cell 159:584\u2013596. https:\/\/doi.org\/10.1016\/j.cell.2014.09.025","journal-title":"Cell"},{"key":"5903_CR10","doi-asserted-by":"publisher","first-page":"6089","DOI":"10.1523\/JNEUROSCI.16-19-06089.1996","volume":"16","author":"X Yang","year":"1996","unstructured":"Yang X, Cepko CL (1996) Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J Neurosci 16:6089\u20136099. https:\/\/doi.org\/10.1523\/JNEUROSCI.16-19-06089.1996","journal-title":"J Neurosci"},{"key":"5903_CR11","doi-asserted-by":"publisher","first-page":"4213","DOI":"10.1172\/JCI65157","volume":"122","author":"T Kurihara","year":"2012","unstructured":"Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M (2012) Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 122:4213\u20134217. https:\/\/doi.org\/10.1172\/JCI65157","journal-title":"J Clin Invest"},{"key":"5903_CR12","doi-asserted-by":"publisher","first-page":"3127","DOI":"10.1016\/j.ejca.2006.09.015","volume":"42","author":"FA Eskens","year":"2006","unstructured":"Eskens FA, Verweij J (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer 42:3127\u20133139. https:\/\/doi.org\/10.1016\/j.ejca.2006.09.015","journal-title":"Eur J Cancer"},{"key":"5903_CR13","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1080\/14712598.2022.2100694","volume":"22","author":"G Uludag","year":"2022","unstructured":"Uludag G et al (2022) Efficacy and safety of intravitreal anti-VEGF therapy in diabetic retinopathy: what we have learned and what should we learn further? Expert Opin Biol Ther 22:1275\u20131291. https:\/\/doi.org\/10.1080\/14712598.2022.2100694","journal-title":"Expert Opin Biol Ther"},{"key":"5903_CR14","doi-asserted-by":"publisher","unstructured":"Simmonds M et al (2025) Anti-VEGF drugs compared with laser photocoagulation for the treatment of proliferative diabetic retinopathy: a systematic review and individual participant data meta-analysis. Health Technol Assess 1\u201375. https:\/\/doi.org\/10.3310\/MJYP6578","DOI":"10.3310\/MJYP6578"},{"key":"5903_CR15","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1056\/NEJMoa054481","volume":"355","author":"PJ Rosenfeld","year":"2006","unstructured":"Rosenfeld PJ et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419\u20131431. https:\/\/doi.org\/10.1056\/NEJMoa054481","journal-title":"N Engl J Med"},{"key":"5903_CR16","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/S0140-6736(22)00010-1","volume":"399","author":"JS Heier","year":"2022","unstructured":"Heier JS et al (2022) Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 399:729\u2013740. https:\/\/doi.org\/10.1016\/S0140-6736(22)00010-1","journal-title":"Lancet"},{"key":"5903_CR17","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adn8388","volume":"16","author":"LH Geraldo","year":"2024","unstructured":"Geraldo LH et al (2024) Monoclonal antibodies that block roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells. Sci Transl Med 16:eadn8388. https:\/\/doi.org\/10.1126\/scitranslmed.adn8388","journal-title":"Sci Transl Med"},{"key":"5903_CR18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nature03080","volume":"432","author":"X Lu","year":"2004","unstructured":"Lu X et al (2004) The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432:179\u2013186. https:\/\/doi.org\/10.1038\/nature03080","journal-title":"Nature"},{"key":"5903_CR19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2408674121","volume":"121","author":"J Furtado","year":"2024","unstructured":"Furtado J et al (2024) Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood-retina barrier integrity. Proc Natl Acad Sci U S A 121:e2408674121. https:\/\/doi.org\/10.1073\/pnas.2408674121","journal-title":"Proc Natl Acad Sci U S A"},{"key":"5903_CR20","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.cmet.2013.02.003","volume":"17","author":"F Binet","year":"2013","unstructured":"Binet F et al (2013) Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1alpha degradation of netrin-1. Cell Metab 17:353\u2013371. https:\/\/doi.org\/10.1016\/j.cmet.2013.02.003","journal-title":"Cell Metab"},{"key":"5903_CR21","doi-asserted-by":"publisher","first-page":"6363","DOI":"10.2147\/DDDT.S93166","volume":"9","author":"Y Yu","year":"2015","unstructured":"Yu Y et al (2015) Effects of intravitreal injection of netrin-1 in retinal neovascularization of streptozotocin-induced diabetic rats. Drug Des Devel Ther 9:6363\u20136377. https:\/\/doi.org\/10.2147\/DDDT.S93166","journal-title":"Drug Des Devel Ther"},{"key":"5903_CR22","doi-asserted-by":"publisher","first-page":"3006","DOI":"10.1172\/JCI84767","volume":"126","author":"K Miloudi","year":"2016","unstructured":"Miloudi K et al (2016) Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy. J Clin Invest 126:3006\u20133022. https:\/\/doi.org\/10.1172\/JCI84767","journal-title":"J Clin Invest"},{"key":"5903_CR23","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1093\/brain\/awv092","volume":"138","author":"C Podjaski","year":"2015","unstructured":"Podjaski C et al (2015) Netrin 1 regulates blood-brain barrier function and neuroinflammation. Brain 138:1598\u20131612. https:\/\/doi.org\/10.1093\/brain\/awv092","journal-title":"Brain"},{"key":"5903_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28785-9","volume":"13","author":"K Boye","year":"2022","unstructured":"Boye K et al (2022) Endothelial Unc5B controls blood-brain barrier integrity. Nat Commun 13:1169. https:\/\/doi.org\/10.1038\/s41467-022-28785-9","journal-title":"Nat Commun"},{"key":"5903_CR25","doi-asserted-by":"publisher","first-page":"13603","DOI":"10.1038\/s41598-024-64375-z","volume":"14","author":"Q Raza","year":"2024","unstructured":"Raza Q et al (2024) Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching. Sci Rep 14:13603. https:\/\/doi.org\/10.1038\/s41598-024-64375-z","journal-title":"Sci Rep"},{"key":"5903_CR26","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1158\/0008-5472.CAN-18-1590","volume":"80","author":"A Boussouar","year":"2020","unstructured":"Boussouar A et al (2020) Netrin-1 and its receptor DCC are causally implicated in melanoma progression. Cancer Res 80:747\u2013756. https:\/\/doi.org\/10.1158\/0008-5472.CAN-18-1590","journal-title":"Cancer Res"},{"key":"5903_CR27","doi-asserted-by":"publisher","first-page":"3230","DOI":"10.1172\/JCI75181","volume":"124","author":"I Brunet","year":"2014","unstructured":"Brunet I et al (2014) Netrin-1 controls sympathetic arterial innervation. J Clin Invest 124:3230\u20133240. https:\/\/doi.org\/10.1172\/JCI75181","journal-title":"J Clin Invest"},{"key":"5903_CR28","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1379-23.2024","author":"C Hanke-Gogokhia","year":"2024","unstructured":"Hanke-Gogokhia C et al (2024) The structural and functional integrity of rod photoreceptor ribbon synapses depends on redundant actions of dynamins 1 and 3. J Neurosci. https:\/\/doi.org\/10.1523\/JNEUROSCI.1379-23.2024","journal-title":"J Neurosci"},{"issue":"2237\u20132251","key":"5903_CR29","doi-asserted-by":"publisher","first-page":"e2236","DOI":"10.1016\/j.devcel.2021.06.021","volume":"56","author":"G Zarkada","year":"2021","unstructured":"Zarkada G et al (2021) Specialized endothelial tip cells guide neuroretina vascularization and blood-retina-barrier formation. Dev Cell 56(2237\u20132251):e2236. https:\/\/doi.org\/10.1016\/j.devcel.2021.06.021","journal-title":"Dev Cell"},{"issue":"1325\u20131333","key":"5903_CR30","doi-asserted-by":"publisher","first-page":"e1323","DOI":"10.1016\/j.neuron.2017.02.043","volume":"93","author":"BW Chow","year":"2017","unstructured":"Chow BW, Gu C (2017) Gradual suppression of transcytosis governs functional blood-retinal barrier formation. Neuron 93(1325\u20131333):e1323. https:\/\/doi.org\/10.1016\/j.neuron.2017.02.043","journal-title":"Neuron"},{"key":"5903_CR31","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1126\/science.1124704","volume":"313","author":"BD Wilson","year":"2006","unstructured":"Wilson BD et al (2006) Netrins promote developmental and therapeutic angiogenesis. Science 313:640\u2013644. https:\/\/doi.org\/10.1126\/science.1124704","journal-title":"Science"},{"key":"5903_CR32","doi-asserted-by":"publisher","first-page":"16210","DOI":"10.1073\/pnas.0405984101","volume":"101","author":"KW Park","year":"2004","unstructured":"Park KW et al (2004) The axonal attractant Netrin-1 is an angiogenic factor. Proc Natl Acad Sci U S A 101:16210\u201316215. https:\/\/doi.org\/10.1073\/pnas.0405984101","journal-title":"Proc Natl Acad Sci U S A"},{"key":"5903_CR33","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1101\/gad.437807","volume":"21","author":"B Larrivee","year":"2007","unstructured":"Larrivee B et al (2007) Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes Dev 21:2433\u20132447. https:\/\/doi.org\/10.1101\/gad.437807","journal-title":"Genes Dev"},{"key":"5903_CR34","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.devcel.2010.12.001","volume":"20","author":"AW Koch","year":"2011","unstructured":"Koch AW et al (2011) Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev Cell 20:33\u201346. https:\/\/doi.org\/10.1016\/j.devcel.2010.12.001","journal-title":"Dev Cell"},{"key":"5903_CR35","first-page":"101","volume":"35","author":"LE Smith","year":"1994","unstructured":"Smith LE et al (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101\u2013111","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"5903_CR36","doi-asserted-by":"publisher","first-page":"1726","DOI":"10.1016\/j.ajpath.2011.12.033","volume":"180","author":"FM Mowat","year":"2012","unstructured":"Mowat FM et al (2012) Endogenous erythropoietin protects neuroretinal function in ischemic retinopathy. Am J Pathol 180:1726\u20131739. https:\/\/doi.org\/10.1016\/j.ajpath.2011.12.033","journal-title":"Am J Pathol"},{"key":"5903_CR37","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1038\/nprot.2009.187","volume":"4","author":"KM Connor","year":"2009","unstructured":"Connor KM et al (2009) Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 4:1565\u20131573. https:\/\/doi.org\/10.1038\/nprot.2009.187","journal-title":"Nat Protoc"},{"key":"5903_CR38","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1016\/S0002-9440(10)65753-7","volume":"153","author":"T Tobe","year":"1998","unstructured":"Tobe T et al (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 153:1641\u20131646. https:\/\/doi.org\/10.1016\/S0002-9440(10)65753-7","journal-title":"Am J Pathol"},{"key":"5903_CR39","doi-asserted-by":"publisher","first-page":"3880","DOI":"10.1167\/iovs.10-6266","volume":"52","author":"A Giani","year":"2011","unstructured":"Giani A et al (2011) In vivo evaluation of laser-induced choroidal neovascularization using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 52:3880\u20133887. https:\/\/doi.org\/10.1167\/iovs.10-6266","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"5903_CR40","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1159\/000324474","volume":"226","author":"XF Tian","year":"2011","unstructured":"Tian XF et al (2011) Netrin-1 overexpression in oxygen-induced retinopathy correlates with breakdown of the blood-retina barrier and retinal neovascularization. Ophthalmologica 226:37\u201344. https:\/\/doi.org\/10.1159\/000324474","journal-title":"Ophthalmologica"},{"key":"5903_CR41","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1159\/000331428","volume":"47","author":"H Xu","year":"2012","unstructured":"Xu H, Liu J, Xiong S, Le YZ, Xia X (2012) Suppression of retinal neovascularization by lentivirus-mediated netrin-1 small hairpin RNA. Ophthalmic Res 47:163\u2013169. https:\/\/doi.org\/10.1159\/000331428","journal-title":"Ophthalmic Res"},{"key":"5903_CR42","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/1471-2415-14-102","volume":"14","author":"D Liu","year":"2014","unstructured":"Liu D et al (2014) Expression of netrin-1 receptors in retina of oxygen-induced retinopathy in mice. BMC Ophthalmol 14:102. https:\/\/doi.org\/10.1186\/1471-2415-14-102","journal-title":"BMC Ophthalmol"},{"key":"5903_CR43","doi-asserted-by":"publisher","first-page":"18828","DOI":"10.1038\/srep18828","volume":"6","author":"N Kociok","year":"2016","unstructured":"Kociok N et al (2016) Lack of netrin-4 modulates pathologic neovascularization in the eye. Sci Rep 6:18828. https:\/\/doi.org\/10.1038\/srep18828","journal-title":"Sci Rep"},{"key":"5903_CR44","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/0092-8674(94)90420-0","volume":"78","author":"T Serafini","year":"1994","unstructured":"Serafini T et al (1994) The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78:409\u2013424. https:\/\/doi.org\/10.1016\/0092-8674(94)90420-0","journal-title":"Cell"},{"key":"5903_CR45","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1016\/s0092-8674(00)81795-x","volume":"87","author":"T Serafini","year":"1996","unstructured":"Serafini T et al (1996) Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87:1001\u20131014. https:\/\/doi.org\/10.1016\/s0092-8674(00)81795-x","journal-title":"Cell"},{"key":"5903_CR46","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/386833a0","volume":"386","author":"ED Leonardo","year":"1997","unstructured":"Leonardo ED et al (1997) Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386:833\u2013838. https:\/\/doi.org\/10.1038\/386833a0","journal-title":"Nature"},{"key":"5903_CR47","doi-asserted-by":"publisher","first-page":"13517","DOI":"10.1038\/ncomms13517","volume":"7","author":"F Zhang","year":"2016","unstructured":"Zhang F et al (2016) The robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization. Nat Commun 7:13517. https:\/\/doi.org\/10.1038\/ncomms13517","journal-title":"Nat Commun"},{"key":"5903_CR48","doi-asserted-by":"publisher","first-page":"2920","DOI":"10.1038\/emboj.2011.189","volume":"30","author":"S Yamagishi","year":"2011","unstructured":"Yamagishi S et al (2011) FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO J 30:2920\u20132933. https:\/\/doi.org\/10.1038\/emboj.2011.189","journal-title":"EMBO J"},{"key":"5903_CR49","doi-asserted-by":"publisher","first-page":"2392","DOI":"10.1242\/dev.149757","volume":"144","author":"I Tai-Nagara","year":"2017","unstructured":"Tai-Nagara I et al (2017) Placental labyrinth formation in mice requires endothelial FLRT2\/UNC5B signaling. Development 144:2392\u20132401. https:\/\/doi.org\/10.1242\/dev.149757","journal-title":"Development"},{"key":"5903_CR50","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.neuron.2014.10.008","volume":"84","author":"E Seiradake","year":"2014","unstructured":"Seiradake E et al (2014) FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron 84:370\u2013385. https:\/\/doi.org\/10.1016\/j.neuron.2014.10.008","journal-title":"Neuron"},{"key":"5903_CR51","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/cr.2015.15","volume":"25","author":"T Tu","year":"2015","unstructured":"Tu T et al (2015) CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development. Cell Res 25:275\u2013287. https:\/\/doi.org\/10.1038\/cr.2015.15","journal-title":"Cell Res"},{"key":"5903_CR52","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1007\/s11427-023-2427-x","volume":"67","author":"B Xue","year":"2024","unstructured":"Xue B et al (2024) Erratum to: CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases. Sci China Life Sci 67:434. https:\/\/doi.org\/10.1007\/s11427-023-2427-x","journal-title":"Sci China Life Sci"},{"key":"5903_CR53","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.bcp.2019.04.029","volume":"164","author":"M Campbell","year":"2019","unstructured":"Campbell M, Doyle SL (2019) Current perspectives on established and novel therapies for pathological neovascularization in retinal disease. Biochem Pharmacol 164:321\u2013325. https:\/\/doi.org\/10.1016\/j.bcp.2019.04.029","journal-title":"Biochem Pharmacol"},{"key":"5903_CR54","doi-asserted-by":"publisher","unstructured":"Jiang G, Han X, Qiao K, Liu S (2022) Therapeutic effect of intravitreal anti-VEGF drugs on retinal neovascularization in diabetic retinopathy. Minerva Med. https:\/\/doi.org\/10.23736\/S0026-4806.22.07943-5","DOI":"10.23736\/S0026-4806.22.07943-5"},{"key":"5903_CR55","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1080\/07853890.2022.2064541","volume":"54","author":"A Arrigo","year":"2022","unstructured":"Arrigo A, Aragona E, Bandello F (2022) VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy. Ann Med 54:1089\u20131111. https:\/\/doi.org\/10.1080\/07853890.2022.2064541","journal-title":"Ann Med"},{"key":"5903_CR56","doi-asserted-by":"publisher","first-page":"e13977","DOI":"10.15252\/emmm.202113977","volume":"13","author":"R Chidiac","year":"2021","unstructured":"Chidiac R et al (2021) A norrin\/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy. EMBO Mol Med 13:e13977. https:\/\/doi.org\/10.15252\/emmm.202113977","journal-title":"EMBO Mol Med"},{"key":"5903_CR57","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/nature22306","volume":"545","author":"CY Janda","year":"2017","unstructured":"Janda CY et al (2017) Surrogate Wnt agonists that phenocopy canonical Wnt and \u03b2-catenin signalling. Nature 545:234\u2013237. https:\/\/doi.org\/10.1038\/nature22306","journal-title":"Nature"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-025-05903-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-025-05903-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-025-05903-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T13:57:52Z","timestamp":1762437472000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-025-05903-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["5903"],"URL":"https:\/\/doi.org\/10.1007\/s00018-025-05903-6","relation":{},"ISSN":["1420-9071"],"issn-type":[{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]},"assertion":[{"value":"14 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All protocols and experimental procedures were approved by the Yale University Institutional Animal Care and Use Committee (IACUC).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"No human subjects were involved in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"No human subjects were involved in this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"AE and KB are Inventors of US Patent App. 18\/573,775, US Patent App. 18\/573,728 and scientific co-founders of D2B3.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"389"}}