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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:p>\n                    Variants in the gene\n                    <jats:italic>NDP<\/jats:italic>\n                    cause Norrie disease, a severe dual-sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death.\n                    <jats:italic>NDP<\/jats:italic>\n                    encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood. We investigated whether the Norrie disease cochlear pathology can be ameliorated in an\n                    <jats:italic>Ndp<\/jats:italic>\n                    -knockout (\n                    <jats:italic>Ndp<\/jats:italic>\n                    -KO) mouse model by conditional activation of stabilized \u03b2-catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, \u03b2-catenin is the primary downstream intracellular effector of norrin binding to endothelial cell surface receptors and that restoration of this signaling pathway is sufficient to prevent sensory hair cell death and hearing loss. We show that tamoxifen induction of\n                    <jats:italic>\n                      Cdh5CreERT2;Ctnnb1\n                      <jats:sup>flex3\/+<\/jats:sup>\n                      ;Ndp-\n                    <\/jats:italic>\n                    KO mice stabilizing \u03b2-catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers (\n                    <jats:italic>Cldn5, Abcb1a, Slc7a1,<\/jats:italic>\n                    and\n                    <jats:italic>Slc7a5<\/jats:italic>\n                    ), and prevented progressive outer hair cell death and hearing loss. Single-cell transcriptome profiling of human cochleas showed\n                    <jats:italic>NDP<\/jats:italic>\n                    expression by fibrocytes and glial cells while receptor gene expression (\n                    <jats:italic>FZD4, TSPAN12, LRP5,<\/jats:italic>\n                    and\n                    <jats:italic>LRP6<\/jats:italic>\n                    ) coincided in vascular endothelial cells. Our findings support the conclusion that vascular endothelial cells are a primary target of norrin signaling in the cochlea of mice and humans and restoration of \u03b2-catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2322124121","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T15:00:38Z","timestamp":1732546838000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease"],"prefix":"10.1073","volume":"121","author":[{"given":"Aara","family":"Patel","sequence":"first","affiliation":[{"name":"Developmental Biology and Cancer Department, University College London Great Ormond Street Institute of Child Health, University College London, and National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7352-7894","authenticated-orcid":false,"given":"Valda","family":"Pauzuolyte","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Department, University College London Great Ormond Street Institute of Child Health, University College London, and National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0916-7347","authenticated-orcid":false,"given":"Neil J.","family":"Ingham","sequence":"additional","affiliation":[{"name":"Wolfson Sensory, Pain and Regeneration Centre, King\u2019s College","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeh Chwan","family":"Leong","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Department, University College London Great Ormond Street Institute of Child Health, University College London, and National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Berger","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Genetics and Zurich Center for Integrative Human Physiology, and Neuroscience Center Zurich, University and ETH Zurich, University of Z\u00fcrich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-5359","authenticated-orcid":false,"given":"Karen P.","family":"Steel","sequence":"additional","affiliation":[{"name":"Wolfson Sensory, Pain and Regeneration Centre, King\u2019s College","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane C.","family":"Sowden","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Department, University College London Great Ormond Street Institute of Child Health, University College London, and National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00216-8"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.07.047"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.07.048"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.06.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06554"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76431"},{"key":"e_1_3_4_7_2","first-page":"2060","article-title":"Multi-functional norrin is a ligand for the LGR4 receptor","volume":"126","author":"Deng C.","year":"2013","unstructured":"C. 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