{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:28:07Z","timestamp":1785803287401,"version":"3.56.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Retinal neurodegeneration, characterized by retinal ganglion cell (RGC) death, is a leading cause of vision impairment and loss in blind diseases, such as glaucoma. M\u00fcller cells play crucial roles in maintaining retinal homeostasis. Thus, dysfunction of M\u00fcller cells has been implicated as one of the causes of retinal diseases. Yes-associated protein 1 (YAP), a nuclear effector of the Hippo pathway, regulates mammalian cell survival. In this study, we investigated the role of YAP in M\u00fcller cells during <jats:italic>N<\/jats:italic>-methyl-D-aspartic acid (NMDA)-induced excitotoxic RGC injury in rats. We found that YAP expression increased and was activated in M\u00fcller cells after NMDA-induced RGC injury. This YAP response was partly due to an increase in <jats:italic>Yap<\/jats:italic> mRNA levels, although it may be independent of the Hippo pathway and \u03b2-TrCP-mediated YAP degradation. Morphological analysis revealed that verteporfin, a selective YAP inhibitor, exacerbated NMDA-induced RGC degeneration, suggesting that YAP activation in M\u00fcller cells contributes to RGC survival in NMDA-treated retinas. Studies in the rat M\u00fcller cell line (rMC-1) demonstrated that overexpression of YAP increased the levels of Bcl-xL, while verteporfin decreased the levels of Bcl-xL and cell viability and increased the levels of cytochrome c released from mitochondria and cleaved caspase-3. Finally, we found that Bcl-xL expression increased slightly in NMDA-treated retinas, whereas intravitreal injection of verteporfin suppressed this increase. Our findings suggest that activated YAP in M\u00fcller cells protects against NMDA-induced RGC injury by upregulating Bcl-xL expression.<\/jats:p>","DOI":"10.3389\/fphar.2024.1446521","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T04:27:22Z","timestamp":1722918442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["YAP activation in M\u00fcller cells protects against NMDA-induced retinal ganglion cell injury by regulating Bcl-xL expression"],"prefix":"10.3389","volume":"15","author":[{"given":"Toshihide","family":"Kashihara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Morita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misaki","family":"Hatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sae","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yume","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akane","family":"Morita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Nakahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"549","DOI":"10.3109\/02713683.2014.933851","article-title":"Age-dependent changes in the severity of capillary degeneration in rat retina following N-methyl-D-aspartate-induced neurotoxicity","volume":"40","author":"Asami","year":"2015","journal-title":"Curr. Eye Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.3390\/ijms21072262","article-title":"Neuroprotective strategies for retinal ganglion cell degeneration: current status and challenges ahead","volume":"21","author":"Boia","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.preteyeres.2006.05.003","article-title":"M\u00fcller cells in the healthy and diseased retina","volume":"25","author":"Bringmann","year":"2006","journal-title":"Prog. Retin. Eye Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000328979","article-title":"M\u00fcller glial cells in retinal disease","volume":"227","author":"Bringmann","year":"2012","journal-title":"Int. J. Ophthalmol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"673599","DOI":"10.3389\/fcell.2021.673599","article-title":"Mechanoregulation of YAP and TAZ in cellular homeostasis and disease progression","volume":"9","author":"Cai","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"617","DOI":"10.3390\/antiox11040617","article-title":"Contribution of M\u00fcller cells in the diabetic retinopathy development: focus on oxidative stress and inflammation","volume":"11","author":"Carpi-Santos","year":"2022","journal-title":"Antioxidants Basel, Switz."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3977","DOI":"10.1074\/jbc.M112.436311","article-title":"Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury","volume":"288","author":"Del","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.14670\/HH-18.1205","article-title":"Role of M\u00fcller glia in neuroprotection and regeneration in the retina","volume":"18","author":"Garc\u00eda","year":"2003","journal-title":"Histol. Histopathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1002\/ijc.32667","article-title":"Verteporfin targeting YAP1\/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells","volume":"146","author":"Giraud","year":"2020","journal-title":"Int. J. Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e8699","DOI":"10.15252\/emmm.201708699","article-title":"Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis","volume":"10","author":"Greenhough","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1097\/ICU.0b013e3280895aea","article-title":"Glaucoma as a neurodegenerative disease","volume":"18","author":"Gupta","year":"2007","journal-title":"Curr. Opin. Ophthalmol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1167\/iovs.16-21366","article-title":"Retinal degeneration triggers the activation of YAP\/TEAD in reactive M\u00fcller cells","volume":"58","author":"Hamon","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e150595","DOI":"10.1172\/JCI150595","article-title":"YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload","volume":"132","author":"Kashihara","year":"2022","journal-title":"J. Clin. Invest."},{"key":"B14","doi-asserted-by":"publisher","first-page":"386","DOI":"10.3390\/ijms23010386","article-title":"The role of inflammation in retinal neurodegeneration and degenerative diseases","volume":"23","author":"Kaur","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"502","DOI":"10.5483\/BMBRep.2023-0059","article-title":"Photobiomodulation therapy activates YAP and triggers proliferation and dedifferentiation of M\u00fcller glia in mammalian retina","volume":"56","author":"Kim","year":"2023","journal-title":"BMB Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.cmet.2018.07.010","article-title":"Interplay between YAP\/TAZ and metabolism","volume":"28","author":"Koo","year":"2018","journal-title":"Cell Metabol."},{"key":"B17","first-page":"2391","article-title":"N-methyl-D-aspartate (NMDA)--induced apoptosis in rat retina","volume":"40","author":"Lam","year":"1999","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"746","DOI":"10.18240\/ijo.2019.05.08","article-title":"Dose-dependent effects of NMDA on retinal and optic nerve morphology in rats","volume":"12","author":"Lambuk","year":"2019","journal-title":"Int. J. Ophthalmol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e40167","DOI":"10.7554\/eLife.40167","article-title":"Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation","volume":"7","author":"LeBlanc","year":"2018","journal-title":"eLife"},{"key":"B20","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1002\/dvdy.24628","article-title":"Hippo-yap signaling in ocular development and disease","volume":"247","author":"Lee","year":"2018","journal-title":"Dev. Dynam"},{"key":"B21","doi-asserted-by":"publisher","first-page":"469","DOI":"10.3389\/fnins.2015.00469","article-title":"Chronic glutamate toxicity in neurodegenerative diseases-What is the evidence?","volume":"9","author":"Lewerenz","year":"2015","journal-title":"Front. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1167\/iovs.09-4159","article-title":"Retinal glial (M\u00fcller) cells: sensing and responding to tissue stretch","volume":"51","author":"Lindqvist","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1101\/gad.192856.112","article-title":"Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP","volume":"26","author":"Liu-Chittenden","year":"2012","journal-title":"Genes Dev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"667796","DOI":"10.3389\/fcell.2021.667796","article-title":"Yap regulates M\u00fcller glia reprogramming in damaged Zebrafish retinas","volume":"9","author":"Louren\u00e7o","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1167\/iovs.02-0187","article-title":"Divergent NMDA signals leading to proapoptotic and antiapoptotic pathways in the rat retina","volume":"44","author":"Manabe","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1038\/s41419-020-02860-9","article-title":"Yap haploinsufficiency leads to M\u00fcller cell dysfunction and late-onset cone dystrophy","volume":"11","author":"Masson","year":"2020","journal-title":"Cell Death Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.trecan.2019.02.010","article-title":"YAP\/TAZ signaling and resistance to cancer therapy","volume":"5","author":"Nguyen","year":"2019","journal-title":"Trends Cancer"},{"key":"B28","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1002\/glia.22477","article-title":"New functions of M\u00fcller cells","volume":"61","author":"Reichenbach","year":"2013","journal-title":"Glia"},{"key":"B29","doi-asserted-by":"publisher","first-page":"164","DOI":"10.2174\/157015908784533851","article-title":"Neurodegenerative diseases of the retina and potential for protection and recovery","volume":"6","author":"Schmidt","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"9189","DOI":"10.2147\/OTT.S217041","article-title":"RASSF6 is downregulated in human bladder cancers and regulates doxorubicin sensitivity and mitochondrial membrane potential via the hippo signaling pathway","volume":"12","author":"Tan","year":"2019","journal-title":"Onco Targets Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1046\/j.1365-2443.1998.00223.x","article-title":"Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?","volume":"3","author":"Tsujimoto","year":"1998","journal-title":"Genes cells."},{"key":"B32","doi-asserted-by":"publisher","first-page":"100599","DOI":"10.1016\/j.jbc.2021.100599","article-title":"S1P induces proliferation of pulmonary artery smooth muscle cells by promoting YAP-induced Notch3 expression and activation","volume":"296","author":"Wang","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4439","DOI":"10.3390\/ijms22094439","article-title":"Metformin protects against NMDA-induced retinal Injury through the MEK\/ERK signaling pathway in rats","volume":"22","author":"Watanabe","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.1002\/jcp.30757","article-title":"Specific ablation of Hippo signalling component Yap1 in retinal progenitors and M\u00fcller cells results in late onset retinal degeneration","volume":"237","author":"Yang","year":"2022","journal-title":"J. Cell Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","article-title":"Hippo pathway in organ size control, tissue homeostasis, and cancer","volume":"163","author":"Yu","year":"2015","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1101\/gad.1843810","article-title":"A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP)","volume":"24","author":"Zhao","year":"2010","journal-title":"Genes Dev."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1446521\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T04:27:25Z","timestamp":1722918445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1446521\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,6]]},"references-count":36,"alternative-id":["10.3389\/fphar.2024.1446521"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1446521","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,6]]},"article-number":"1446521"}}