{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:27:09Z","timestamp":1789720029980,"version":"4.0.1"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Norrin is a secreted signaling molecule activating the Wnt\/\u03b2-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA\/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA\/2J\/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA\/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA\/2J\/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA\/2J\/Pax6-Norrin mice, which showed a \u03b2-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt\/\u03b2-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.<\/jats:p>","DOI":"10.1038\/s41598-017-14423-8","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T19:35:29Z","timestamp":1508787329000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma"],"prefix":"10.1038","volume":"7","author":[{"given":"Stephanie A.","family":"Leopold","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwig F.","family":"Zeilbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roswitha","family":"Seitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"B\u00f6sl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"J\u00e4gle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Fuchshofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst R.","family":"Tamm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Ohlmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"14423_CR1","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.exer.2011.06.016","volume":"102","author":"A Ohlmann","year":"2012","unstructured":"Ohlmann, A., Merkl, R. & Tamm, E. R. Focus on molecules: norrin. Exp. Eye Res. \n                           102, 109\u2013110 (2012).","journal-title":"Exp. Eye Res."},{"key":"14423_CR2","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.preteyeres.2012.02.002","volume":"31","author":"A Ohlmann","year":"2012","unstructured":"Ohlmann, A. & Tamm, E. R. Norrin: molecular and functional properties of an angiogenic and neuroprotective growth factor. Prog. Retin. Eye Res. \n                           31, 243\u2013257 (2012).","journal-title":"Prog. Retin. Eye Res."},{"key":"14423_CR3","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1101\/gad.228544.113","volume":"27","author":"J Ke","year":"2013","unstructured":"Ke, J. et al. Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5\/6 complex. Genes Dev. \n                           27, 2305\u20132319 (2013).","journal-title":"Genes Dev."},{"key":"14423_CR4","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.gep.2010.10.007","volume":"11","author":"X Ye","year":"2011","unstructured":"Ye, X., Smallwood, P. & Nathans, J. Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain. Gene Expr. Patterns \n                           11, 151\u2013155 (2011).","journal-title":"Gene Expr. Patterns"},{"key":"14423_CR5","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.cell.2009.07.047","volume":"139","author":"X Ye","year":"2009","unstructured":"Ye, X. et al. Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell \n                           139, 285\u2013298 (2009).","journal-title":"Cell"},{"key":"14423_CR6","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/S0092-8674(04)00216-8","volume":"116","author":"Q Xu","year":"2004","unstructured":"Xu, Q. et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell \n                           116, 883\u2013895 (2004).","journal-title":"Cell"},{"key":"14423_CR7","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.cell.2009.07.048","volume":"139","author":"HJ Junge","year":"2009","unstructured":"Junge, H. J. et al. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4\/\u03b2-catenin signaling. Cell \n                           139, 299\u2013311 (2009).","journal-title":"Cell"},{"key":"14423_CR8","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.1523\/JNEUROSCI.22-11-04286.2002","volume":"22","author":"HL Rehm","year":"2002","unstructured":"Rehm, H. L. et al. Vascular defects and sensorineural deafness in a mouse model of Norrie disease. J. Neurosci. \n                           22, 4286\u20134292 (2002).","journal-title":"J. Neurosci."},{"key":"14423_CR9","first-page":"2450","volume":"39","author":"M Richter","year":"1998","unstructured":"Richter, M. et al. Retinal vasculature changes in Norrie disease mice. Invest. Ophthalmol. Vis. Sci. \n                           39, 2450\u20132457 (1998).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR10","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1523\/JNEUROSCI.4756-04.2005","volume":"25","author":"A Ohlmann","year":"2005","unstructured":"Ohlmann, A. et al. Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. J. Neurosci. \n                           25, 1701\u20131710 (2005).","journal-title":"J. Neurosci."},{"key":"14423_CR11","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1523\/JNEUROSCI.3210-09.2010","volume":"30","author":"A Ohlmann","year":"2010","unstructured":"Ohlmann, A. et al. Norrin promotes vascular regrowth after oxygen-induced retinal vessel loss and suppresses retinopathy in mice. J. Neurosci. \n                           30, 183\u2013193 (2010).","journal-title":"J. Neurosci."},{"key":"14423_CR12","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.exer.2015.12.001","volume":"145","author":"LF Zeilbeck","year":"2016","unstructured":"Zeilbeck, L. F. et al. Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1. Exp. Eye Res. \n                           145, 317\u2013326 (2016).","journal-title":"Exp. Eye Res."},{"key":"14423_CR13","doi-asserted-by":"publisher","first-page":"8314","DOI":"10.1167\/iovs.15-18359","volume":"56","author":"JW Han","year":"2015","unstructured":"Han, J. W., Lyu, J., Park, Y. J., Jang, S. Y. & Park, T. K. Wnt\/\u03b2-Catenin Signaling Mediates Regeneration of Retinal Pigment Epithelium After Laser Photocoagulation in Mouse Eye. Invest. Ophthalmol. Vis. Sci. \n                           56, 8314\u20138324 (2015).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR14","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.neuroscience.2016.12.020","volume":"343","author":"AK Patel","year":"2017","unstructured":"Patel, A. K., Park, K. K. & Hackam, A. S. Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse. Neuroscience \n                           343, 372\u2013383 (2017).","journal-title":"Neuroscience"},{"key":"14423_CR15","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1167\/iovs.12-10774","volume":"54","author":"B Liu","year":"2013","unstructured":"Liu, B. et al. Wnt signaling promotes Muller cell proliferation and survival after injury. Invest. Ophthalmol. Vis. Sci. \n                           54, 444\u2013453 (2013).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR16","first-page":"2825","volume":"43","author":"S Lenzner","year":"2002","unstructured":"Lenzner, S. et al. Global gene expression analysis in a mouse model for Norrie disease: late involvement of photoreceptor cells. Invest. Ophthalmol. Vis. Sci. \n                           43, 2825\u20132833 (2002).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR17","first-page":"24","volume":"4","author":"SL Bernstein","year":"1998","unstructured":"Bernstein, S. L. & Wong, P. Regional expression of disease-related genes in human and monkey retina. Mol. Vis. \n                           4, 24 (1998).","journal-title":"Mol. Vis."},{"key":"14423_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.nbd.2012.09.008","volume":"50","author":"BM Braunger","year":"2013","unstructured":"Braunger, B. M. et al. Constitutive overexpression of Norrin activates Wnt\/\u03b2-catenin and endothelin-2 signaling to protect photoreceptors from light damage. Neurobiol. Dis. \n                           50, 1\u201312 (2013).","journal-title":"Neurobiol. Dis."},{"key":"14423_CR19","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/978-1-62703-080-9_6","volume":"935","author":"C Grimm","year":"2013","unstructured":"Grimm, C. & Reme, C. E. Light damage as a model of retinal degeneration. Methods Mol. Biol. \n                           935, 87\u201397 (2013).","journal-title":"Methods Mol. Biol."},{"key":"14423_CR20","doi-asserted-by":"publisher","first-page":"5998","DOI":"10.1523\/JNEUROSCI.0730-10.2010","volume":"30","author":"R Seitz","year":"2010","unstructured":"Seitz, R., Hackl, S., Seibuchner, T., Tamm, E. R. & Ohlmann, A. Norrin mediates neuroprotective effects on retinal ganglion cells via activation of the Wnt\/\u03b2-catenin signaling pathway and the induction of neuroprotective growth factors in Muller cells. J. Neurosci. \n                           30, 5998\u20136010 (2010).","journal-title":"J. Neurosci."},{"key":"14423_CR21","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1007\/978-1-62703-080-9_7","volume":"935","author":"R Seitz","year":"2013","unstructured":"Seitz, R. & Tamm, E. R. N-methyl-D-aspartate (NMDA)-mediated excitotoxic damage: a mouse model of acute retinal ganglion cell damage. Methods Mol. Biol. \n                           935, 99\u2013109 (2013).","journal-title":"Methods Mol. Biol."},{"key":"14423_CR22","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/S0140-6736(10)61423-7","volume":"377","author":"HA Quigley","year":"2011","unstructured":"Quigley, H. A. Glaucoma. Lancet \n                           377, 1367\u20131377 (2011).","journal-title":"Lancet"},{"key":"14423_CR23","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1001\/jama.2014.3192","volume":"311","author":"RN Weinreb","year":"2014","unstructured":"Weinreb, R. N., Aung, T. & Medeiros, F. A. The pathophysiology and treatment of glaucoma: a review. JAMA \n                           311, 1901\u20131911 (2014).","journal-title":"JAMA"},{"key":"14423_CR24","first-page":"951","volume":"39","author":"SW John","year":"1998","unstructured":"John, S. W. et al. Essential iris atrophy, pigment dispersion, and glaucoma in DBA\/2J mice. Invest. Ophthalmol. Vis. Sci. \n                           39, 951\u2013962 (1998).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR25","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1017\/S0952523805225130","volume":"22","author":"RT Libby","year":"2005","unstructured":"Libby, R. T. et al. Inherited glaucoma in DBA\/2J mice: pertinent disease features for studying the neurodegeneration. Vis. Neurosci. \n                           22, 637\u2013648 (2005).","journal-title":"Vis. Neurosci."},{"key":"14423_CR26","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.exer.2015.06.019","volume":"141","author":"KA Fernandes","year":"2015","unstructured":"Fernandes, K. A. et al. Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities. Exp. Eye Res. \n                           141, 42\u201356 (2015).","journal-title":"Exp. Eye Res."},{"key":"14423_CR27","first-page":"635","volume":"99","author":"HA Quigley","year":"1981","unstructured":"Quigley, H. A., Addicks, E. M., Green, W. R. & Maumenee, A. E. Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch. Ophthalmol. \n                           99, 635\u2013649 (1981).","journal-title":"The site of injury and susceptibility to damage. Arch. Ophthalmol."},{"key":"14423_CR28","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1083\/jcb.200706181","volume":"179","author":"GR Howell","year":"2007","unstructured":"Howell, G. R. et al. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA\/2J glaucoma. J. Cell Biol. \n                           179, 1523\u20131537 (2007).","journal-title":"J. Cell Biol."},{"key":"14423_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-7-66","volume":"7","author":"CL Schlamp","year":"2006","unstructured":"Schlamp, C. L., Li, Y., Dietz, J. A., Janssen, K. T. & Nickells, R. W. Progressive ganglion cell loss and optic nerve degeneration in DBA\/2J mice is variable and asymmetric. BMC neuroscience \n                           7, 66, https:\/\/doi.org\/10.1186\/1471-2202-7-66 (2006).","journal-title":"BMC neuroscience"},{"key":"14423_CR30","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1093\/hmg\/ddi231","volume":"14","author":"N Davis-Silberman","year":"2005","unstructured":"Davis-Silberman, N. et al. Genetic dissection of Pax6 dosage requirements in the developing mouse eye. Hum. Mol. Genet. \n                           14, 2265\u20132276 (2005).","journal-title":"Hum. Mol. Genet."},{"key":"14423_CR31","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1006\/dbio.1998.9128","volume":"205","author":"B Kammandel","year":"1999","unstructured":"Kammandel, B. et al. Distinct cis-essential modules direct the time-space pattern of the Pax6 gene activity. Dev. Biol. \n                           205, 79\u201397 (1999).","journal-title":"Dev. Biol."},{"key":"14423_CR32","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/S0092-8674(01)00295-1","volume":"105","author":"T Marquardt","year":"2001","unstructured":"Marquardt, T. et al. Pax6 is required for the multipotent state of retinal progenitor cells. Cell \n                           105, 43\u201355 (2001).","journal-title":"Cell"},{"key":"14423_CR33","doi-asserted-by":"publisher","first-page":"14246","DOI":"10.1523\/JNEUROSCI.0991-13.2013","volume":"33","author":"BM Braunger","year":"2013","unstructured":"Braunger, B. M. et al. TGF-\u03b2 signaling protects retinal neurons from programmed cell death during the development of the mammalian eye. J. Neurosci. \n                           33, 14246\u201314258 (2013).","journal-title":"J. Neurosci."},{"key":"14423_CR34","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1016\/j.ajpath.2015.02.007","volume":"185","author":"BM Braunger","year":"2015","unstructured":"Braunger, B. M. et al. Deletion of ocular transforming growth factor-\u03b2 signaling mimics essential characteristics of diabetic retinopathy. Am. J. Pathol. \n                           185, 1749\u20131768 (2015).","journal-title":"Am. J. Pathol."},{"key":"14423_CR35","first-page":"1901","volume":"19","author":"X Yang","year":"2013","unstructured":"Yang, X. et al. IGF-1 protects retinal ganglion cells from hypoxia-induced apoptosis by activating the Erk-1\/2 and Akt pathways. Mol. Vis. \n                           19, 1901\u20131912 (2013).","journal-title":"Mol. Vis."},{"key":"14423_CR36","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1007\/s12031-014-0448-7","volume":"55","author":"H Wang","year":"2015","unstructured":"Wang, H. et al. IGF-1 signaling via the PI3K\/Akt pathway confers neuroprotection in human retinal pigment epithelial cells exposed to sodium nitroprusside insult. J. Mol. Neurosci. \n                           55, 931\u2013940 (2015).","journal-title":"J. Mol. Neurosci."},{"key":"14423_CR37","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1096\/fj.04-1581fje","volume":"18","author":"GM Leinninger","year":"2004","unstructured":"Leinninger, G. M., Backus, C., Uhler, M. D., Lentz, S. I. & Feldman, E. L. Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J. \n                           18, 1544\u20131546 (2004).","journal-title":"FASEB J."},{"key":"14423_CR38","doi-asserted-by":"publisher","first-page":"5151","DOI":"10.1167\/iovs.02-1101","volume":"44","author":"J Danias","year":"2003","unstructured":"Danias, J. et al. Quantitative analysis of retinal ganglion cell (RGC) loss in aging DBA\/2NNia glaucomatous mice: comparison with RGC loss in aging C57\/BL6 mice. Invest. Ophthalmol. Vis. Sci. \n                           44, 5151\u20135162 (2003).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR39","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1002\/cne.22516","volume":"519","author":"A Bosco","year":"2011","unstructured":"Bosco, A., Steele, M. R. & Vetter, M. L. Early microglia activation in a mouse model of chronic glaucoma. J. Comp. Neurol. \n                           519, 599\u2013620 (2011).","journal-title":"J. Comp. Neurol."},{"key":"14423_CR40","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1172\/JCI61135","volume":"122","author":"GR Howell","year":"2012","unstructured":"Howell, G. R. et al. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J. Clin. Invest. \n                           122, 1246\u20131261 (2012).","journal-title":"J. Clin. Invest."},{"key":"14423_CR41","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1084\/jem.20022041","volume":"197","author":"JS Mo","year":"2003","unstructured":"Mo, J. S. et al. By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA\/2J pigmentary glaucoma. J. Exp. Med. \n                           197, 1335\u20131344 (2003).","journal-title":"J. Exp. Med."},{"key":"14423_CR42","doi-asserted-by":"publisher","first-page":"31240","DOI":"10.1074\/jbc.M502641200","volume":"280","author":"X Zhou","year":"2005","unstructured":"Zhou, X. et al. Involvement of inflammation, degradation, and apoptosis in a mouse model of glaucoma. J. Biol. Chem. \n                           280, 31240\u201331248 (2005).","journal-title":"J. Biol. Chem."},{"key":"14423_CR43","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1167\/iovs.05-0830","volume":"47","author":"K Stasi","year":"2006","unstructured":"Stasi, K. et al. Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest. Ophthalmol. Vis. Sci. \n                           47, 1024\u20131029 (2006).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR44","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/ng794","volume":"30","author":"MG Anderson","year":"2002","unstructured":"Anderson, M. G. et al. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA\/2J mice. Nat. Genet. \n                           30, 81\u201385 (2002).","journal-title":"Nat. Genet."},{"key":"14423_CR45","doi-asserted-by":"publisher","first-page":"4540","DOI":"10.1523\/JNEUROSCI.0492-05.2005","volume":"25","author":"A Rattner","year":"2005","unstructured":"Rattner, A. & Nathans, J. The genomic response to retinal disease and injury: evidence for endothelin signaling from photoreceptors to glia. J. Neurosci. \n                           25, 4540\u20134549 (2005).","journal-title":"J. Neurosci."},{"key":"14423_CR46","doi-asserted-by":"publisher","first-page":"2311","DOI":"10.1167\/iovs.06-1205","volume":"48","author":"S Joly","year":"2007","unstructured":"Joly, S., Pernet, V., Chemtob, S., Di Polo, A. & Lachapelle, P. Neuroprotection in the juvenile rat model of light-induced retinopathy: evidence suggesting a role for FGF-2 and CNTF. Invest. Ophthalmol. Vis. Sci. \n                           48, 2311\u20132320 (2007).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR47","doi-asserted-by":"publisher","first-page":"11249","DOI":"10.1073\/pnas.89.23.11249","volume":"89","author":"MM LaVail","year":"1992","unstructured":"LaVail, M. M. et al. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc. Natl. Acad. Sci. USA \n                           89, 11249\u201311253 (1992).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"14423_CR48","first-page":"592","volume":"39","author":"MM LaVail","year":"1998","unstructured":"LaVail, M. M. et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest. Ophthalmol. Vis. Sci. \n                           39, 592\u2013602 (1998).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR49","doi-asserted-by":"publisher","first-page":"13765","DOI":"10.1523\/JNEUROSCI.5114-08.2008","volume":"28","author":"S Joly","year":"2008","unstructured":"Joly, S., Lange, C., Thiersch, M., Samardzija, M. & Grimm, C. Leukemia inhibitory factor extends the lifespan of injured photoreceptors in vivo. J. Neurosci. \n                           28, 13765\u201313774 (2008).","journal-title":"J. Neurosci."},{"key":"14423_CR50","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1172\/JCI44646","volume":"121","author":"GR Howell","year":"2011","unstructured":"Howell, G. R. et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clin. Invest. \n                           121, 1429\u20131444 (2011).","journal-title":"J. Clin. Invest."},{"key":"14423_CR51","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1126\/science.275.5300.661","volume":"275","author":"H Dudek","year":"1997","unstructured":"Dudek, H. et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science \n                           275, 661\u2013665 (1997).","journal-title":"Science"},{"key":"14423_CR52","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S0959-4388(00)00211-7","volume":"11","author":"A Brunet","year":"2001","unstructured":"Brunet, A., Datta, S. R. & Greenberg, M. E. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. \n                           11, 297\u2013305 (2001).","journal-title":"Curr. Opin. Neurobiol."},{"key":"14423_CR53","doi-asserted-by":"publisher","first-page":"2905","DOI":"10.1101\/gad.13.22.2905","volume":"13","author":"SR Datta","year":"1999","unstructured":"Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. \n                           13, 2905\u20132927 (1999).","journal-title":"Genes Dev."},{"key":"14423_CR54","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/S0896-6273(00)00061-1","volume":"27","author":"R Kuruvilla","year":"2000","unstructured":"Kuruvilla, R., Ye, H. & Ginty, D. D. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron \n                           27, 499\u2013512 (2000).","journal-title":"Neuron"},{"key":"14423_CR55","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10633-013-9380-3","volume":"126","author":"J Atorf","year":"2013","unstructured":"Atorf, J. et al. Functional protective effects of long-term memantine treatment in the DBA\/2J mouse. Doc. Ophthalmol. \n                           126, 221\u2013232 (2013).","journal-title":"Doc. Ophthalmol."},{"key":"14423_CR56","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s10633-009-9194-5","volume":"119","author":"J Harazny","year":"2009","unstructured":"Harazny, J., Scholz, M., Buder, T., Lausen, B. & Kremers, J. Electrophysiological deficits in the retina of the DBA\/2J mouse. Doc. Ophthalmol. \n                           119, 181\u2013197 (2009).","journal-title":"Doc. Ophthalmol."},{"key":"14423_CR57","doi-asserted-by":"crossref","unstructured":"Anderson, M. G., Libby, R. T., Gould, D. B., Smith, R. S. & John, S. W. High-dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma. Proc. Natl. Acad. Sci. USA \n                           102 (2005)","DOI":"10.1073\/pnas.0407357102"},{"key":"14423_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2156-8-45","volume":"8","author":"GR Howell","year":"2007","unstructured":"Howell, G. R. et al. Absence of glaucoma in DBA\/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Genet. \n                           8, 45, https:\/\/doi.org\/10.1186\/1471-2156-8-45 (2007).","journal-title":"BMC Genet."},{"key":"14423_CR59","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1146\/annurev.genom.6.080604.162209","volume":"6","author":"RT Libby","year":"2005","unstructured":"Libby, R. T., Gould, D. B., Anderson, M. G. & John, S. W. Complex genetics of glaucoma susceptibility. Annu. Rev. Genomics Hum. Genet. \n                           6, 15\u201344 (2005).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"14423_CR60","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-4-20","volume":"4","author":"MG Anderson","year":"2006","unstructured":"Anderson, M. G. et al. Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma. BMC Biol. \n                           4, 20 (2006).","journal-title":"BMC Biol."},{"key":"14423_CR61","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1167\/iovs.05-0959","volume":"47","author":"A Matsubara","year":"2006","unstructured":"Matsubara, A. et al. Investigating the effect of ciliary body photodynamic therapy in a glaucoma mouse model. Invest. Ophthalmol. Vis. Sci. \n                           47, 2498\u20132507 (2006).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR62","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1016\/S0042-6989(02)00188-8","volume":"42","author":"F Schuettauf","year":"2002","unstructured":"Schuettauf, F., Quinto, K., Naskar, R. & Zurakowski, D. Effects of anti-glaucoma medications on ganglion cell survival: the DBA\/2J mouse model. Vision Res. \n                           42, 2333\u20132337 (2002).","journal-title":"Vision Res."},{"key":"14423_CR63","doi-asserted-by":"publisher","first-page":"5956","DOI":"10.1167\/iovs.12-10020","volume":"53","author":"AA Wong","year":"2012","unstructured":"Wong, A. A. & Brown, R. E. A neurobehavioral analysis of the prevention of visual impairment in the DBA\/2J mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. \n                           53, 5956\u20135966 (2012).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR64","doi-asserted-by":"publisher","first-page":"52","DOI":"10.3389\/fnagi.2013.00052","volume":"5","author":"AA Wong","year":"2013","unstructured":"Wong, A. A. & Brown, R. E. Prevention of vision loss protects against age-related impairment in learning and memory performance in DBA\/2J mice. Front. Aging Neurosci. \n                           5, 52, https:\/\/doi.org\/10.3389\/fnagi.2013.00052 (2013).","journal-title":"Front. Aging Neurosci."},{"key":"14423_CR65","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13024-016-0091-6","volume":"11","author":"PA Williams","year":"2016","unstructured":"Williams, P. A. et al. Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol. Neurodegener. \n                           11, 26, https:\/\/doi.org\/10.1186\/s13024-016-0091-6 (2016).","journal-title":"Mol. Neurodegener."},{"key":"14423_CR66","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.nbd.2014.07.016","volume":"71","author":"GR Howell","year":"2014","unstructured":"Howell, G. R. et al. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol. Dis. \n                           71, 44\u201352 (2014).","journal-title":"Neurobiol. Dis."},{"key":"14423_CR67","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-76","volume":"10","author":"GR Howell","year":"2013","unstructured":"Howell, G. R. et al. Deficiency of complement component 5 ameliorates glaucoma in DBA\/2J mice. J. Neuroinflammation \n                           10, 76, https:\/\/doi.org\/10.1186\/1742-2094-10-76 (2013).","journal-title":"J. Neuroinflammation"},{"key":"14423_CR68","doi-asserted-by":"publisher","first-page":"e43602","DOI":"10.1371\/journal.pone.0043602","volume":"7","author":"A Bosco","year":"2012","unstructured":"Bosco, A. et al. Early reduction of microglia activation by irradiation in a model of chronic glaucoma. PloS one \n                           7, e43602, https:\/\/doi.org\/10.1371\/journal.pone.0043602 (2012).","journal-title":"PloS one"},{"key":"14423_CR69","first-page":"1056","volume":"118","author":"WH Wang","year":"2008","unstructured":"Wang, W. H. et al. Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure. J. Clin. Invest. \n                           118, 1056\u20131064 (2008).","journal-title":"J. Clin. Invest."},{"key":"14423_CR70","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.exer.2015.01.025","volume":"132","author":"JT Morgan","year":"2015","unstructured":"Morgan, J. T., Raghunathan, V. K., Chang, Y. R., Murphy, C. J. & Russell, P. Wnt inhibition induces persistent increases in intrinsic stiffness of human trabecular meshwork cells. Exp. Eye. Res. \n                           132, 174\u2013178 (2015).","journal-title":"Exp. Eye. Res."},{"key":"14423_CR71","doi-asserted-by":"publisher","first-page":"7433","DOI":"10.1167\/iovs.13-12652","volume":"55","author":"G Villarreal Jr.","year":"2014","unstructured":"Villarreal, G. Jr. et al. Canonical wnt signaling regulates extracellular matrix expression in the trabecular meshwork. Invest. Ophthalmol. Vis. Sci. \n                           55, 7433\u20137440 (2014).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"14423_CR72","doi-asserted-by":"publisher","first-page":"3332","DOI":"10.1093\/hmg\/ddq237","volume":"19","author":"M Kroeber","year":"2010","unstructured":"Kroeber, M. et al. Reduced expression of Pax6 in lens and cornea of mutant mice leads to failure of chamber angle development and juvenile glaucoma. Hum. Mol. Genet. \n                           19, 3332\u20133342 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"14423_CR73","doi-asserted-by":"publisher","first-page":"313","DOI":"10.3109\/10520296009114754","volume":"35","author":"KC Richardson","year":"1960","unstructured":"Richardson, K. C., Jarret, L. & Finke, H. Embedding in epoxy resins for ultrathin sectioning in electron microscopy. Stain. Technol. \n                           35, 313\u2013323 (1960).","journal-title":"Stain. Technol."},{"key":"14423_CR74","first-page":"639","volume":"36","author":"WH\u00dc Schultze","year":"1972","unstructured":"Schultze, W. H. \u00dc. das Paraphenylendiamin in der histologischen F\u00e4rbetechnik und \u00fcber eine neue Schnellf\u00e4rbemethode der Nervenmarkscheide am Gefrierschnitt. Zentralbl. Pathol. \n                           36, 639\u2013640 (1972).","journal-title":"Zentralbl. Pathol."},{"key":"14423_CR75","first-page":"28","volume":"252C","author":"TK Forkwa","year":"2013","unstructured":"Forkwa, T. K., Neumann, I. D., Tamm, E. R., Ohlmann, A. & Reber, S. O. Short-term psychosocial stress protects photoreceptors from damage via corticosterone-mediated activation of the AKT pathway. Exp. Neurol. \n                           252C, 28\u201336 (2013).","journal-title":"Exp. Neurol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14423-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14423-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14423-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T12:42:29Z","timestamp":1671799349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14423-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,27]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["14423"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-14423-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,27]]},"assertion":[{"value":"2 June 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14274"}}