{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:10:21Z","timestamp":1787065821088,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>\n                    Retinal ganglion cells expressing the photopigment melanopsin are intrinsically photosensitive (ipRGCs). ipRGCs regulate subconscious non-image-forming behaviors such as circadian rhythms, pupil dilation, and light-mediated mood. Previously, we and others showed that the transcription factor Tbr2 (EOMES) is required during retinal development for the formation of ipRGCs. Tbr2 is also expressed in the adult retina leading to the hypothesis that it plays a role in adult ipRGC function. To test this, we removed\n                    <jats:italic>Tbr2<\/jats:italic>\n                    in adult mice. We found that this results in the loss of melanopsin expression in ipRGCs but does not lead to cell death or morphological changes to their dendritic or axonal termination patterns. Additionally, we found ectopic expression of Tbr2 in conventional RGCs does not induce melanopsin expression but can increase melanopsin expression in existing ipRGCs. An interesting feature of ipRGCs is their superior survival relative to conventional RGCs after an optic nerve injury. We find that loss of Tbr2 decreases the survival rate of ipRGCs after optic nerve damage suggesting that\n                    <jats:italic>Tbr2<\/jats:italic>\n                    plays a role in ipRGC survival after injury. Lastly, we show that the GABAergic amacrine cell marker Meis2, is expressed in the majority of Tbr2-expressing displaced amacrine cells as well as in a subset of Tbr2-expressing RGCs. These findings demonstrate that\n                    <jats:italic>Tbr2<\/jats:italic>\n                    is necessary but not sufficient for melanopsin expression, that\n                    <jats:italic>Tbr2<\/jats:italic>\n                    is involved in ipRGC survival after optic nerve injury, and identify a marker for Tbr2-expressing displaced amacrine cells.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2022.826590","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T17:09:06Z","timestamp":1648487346000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Adult Expression of Tbr2 Is Required for the Maintenance but Not Survival of Intrinsically Photosensitive Retinal Ganglion Cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Sadaf","family":"Abed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian J.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Feldheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1176\/appi.neuropsych.12020030","article-title":"Depression, Anxiety, and Disturbed Sleep in Glaucoma.","volume":"25","author":"Agorastos","year":"2013","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nature16468","article-title":"The functional diversity of retinal ganglion cells in the mouse.","volume":"529","author":"Baden","year":"2016","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1293.e","DOI":"10.1016\/j.cell.2018.04.040","article-title":"Digital Museum of Retinal Ganglion Cells with Dense Anatomy and Physiology.","volume":"173","author":"Bae","year":"2018","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1126\/science.1067262","article-title":"Phototransduction by retinal ganglion cells that set the circadian clock.","volume":"295","author":"Berson","year":"2002","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.neuron.2019.05.044","article-title":"Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells.","volume":"103","author":"Bray","year":"2019","journal-title":"Neuron"},{"key":"B6","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/cne.21458","article-title":"Expression of the homeodomain transcription factor Meis2 in the embryonic and postnatal retina","volume":"505","author":"Bumsted-O\u2019Brien","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3513","DOI":"10.1002\/cne.25208","article-title":"Characterization of Tbr2-expressing retinal ganglion cells.","volume":"529","author":"Chen","year":"2021","journal-title":"J. Comp. Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/nn.3731","article-title":"Maintenance of postmitotic neuronal cell identity.","volume":"17","author":"Deneris","year":"2014","journal-title":"Nat. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1016\/j.neuron.2015.02.017","article-title":"Subtype-Specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mtor signaling.","volume":"85","author":"Duan","year":"2015","journal-title":"Neuron"},{"key":"B10","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.neuron.2010.05.023","article-title":"Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision.","volume":"67","author":"Ecker","year":"2010","journal-title":"Neuron"},{"key":"B11","doi-asserted-by":"publisher","first-page":"571","DOI":"10.3389\/fnins.2018.00571","article-title":"The epigenetic factor landscape of developing neocortex is regulated by transcription factors Pax6\u2192 Tbr2\u2192 Tbr1.","volume":"12","author":"Elsen","year":"2018","journal-title":"Front. Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4362","DOI":"10.1167\/iovs.10-7069","article-title":"Intrinsically photosensitive (melanopsin) retinal ganglion cell function in glaucoma.","volume":"52","author":"Feigl","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"5317371","DOI":"10.1155\/2016\/5317371","article-title":"Relationship between Daytime Sleepiness and Intrinsically Photosensitive Retinal Ganglion Cells in Glaucomatous Disease.","volume":"2016","author":"Gracitelli","year":"2016","journal-title":"J. Ophthalmol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.1242\/dev.006379","article-title":"Spatial and temporal specification of neural fates by transcription factor codes.","volume":"134","author":"Guillemot","year":"2007","journal-title":"Development"},{"key":"B15","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/nature06829","article-title":"Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision.","volume":"453","author":"G\u00fcler","year":"2008","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e2451","DOI":"10.1371\/journal.pone.0002451","article-title":"Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses.","volume":"3","author":"Hatori","year":"2008","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1126\/science.1069609","article-title":"Melanopsin-Containing Retinal Ganglion Cells: architecture, Projections, and Intrinsic Photosensitivity.","volume":"295","author":"Hattar","year":"2002","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1111\/joa.12939","article-title":"Intermediate progenitors and Tbr2 in cortical development.","volume":"235","author":"Hevner","year":"2019","journal-title":"J. Anat."},{"key":"B19","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nature11673","article-title":"Aberrant light directly impairs mood and learning through melanopsin-expressing neurons.","volume":"491","author":"Legates","year":"2012","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s12859-016-0876-1","article-title":"IPLaminator: an ImageJ plugin for automated binning and quantification of retinal lamination.","volume":"17","author":"Li","year":"2016","journal-title":"BMC Bioinform."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1007\/s10571-008-9286-x","article-title":"Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K \/ Akt Pathway.","volume":"28","author":"Li","year":"2008","journal-title":"Cell Mol. Neurobiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1002\/cne.21126","article-title":"Populations of Wide-Field Amacrine Cells in the Mouse Retina.","volume":"499","author":"Lin","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"109994","DOI":"10.2139\/ssrn.3921283","article-title":"Gene Regulatory Networks Controlling Temporal Patterning, Neurogenesis, and Cell Fate Specification in the Mammalian Retina.","volume":"37","author":"Lyu","year":"2021","journal-title":"SSRN Electron. J."},{"key":"B24","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0896-6273(00)80478-X","article-title":"Extreme Diversity among Amacrine Cells: implications for Function.","volume":"20","author":"MacNeil","year":"1998","journal-title":"Neuron"},{"key":"B25","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre Reporting and characterization system for the whole mouse brain.","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1080\/1536710X.2013.870512.Behavioral","article-title":"Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse.","volume":"135","author":"Mao","year":"2008","journal-title":"Development"},{"key":"B27","doi-asserted-by":"publisher","first-page":"13083","DOI":"10.1523\/JNEUROSCI.1027-14.2014","article-title":"T-box Transcription Regulator Tbr2 Is Essential for the Formation and Maintenance of Opn4\/Melanopsin-Expressing Intrinsically Photosensitive Retinal Ganglion Cells.","volume":"34","author":"Mao","year":"2014","journal-title":"J. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2058","DOI":"10.1016\/j.celrep.2017.01.075","article-title":"Diverse Central Projection Patterns of Retinal Ganglion Cells.","volume":"18","author":"Martersteck","year":"2017","journal-title":"Cell Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"6095","DOI":"10.1167\/iovs.15-17195","article-title":"Long-Term Effect of Optic Nerve Axotomy on the Retinal Ganglion Cell Layer.","volume":"56","author":"Nadal-Nicol\u00e1s","year":"2015","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1126\/science.1076848","article-title":"Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting.","volume":"298","author":"Panda","year":"2002","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"869.e","DOI":"10.1016\/j.neuron.2017.07.019","article-title":"Satb1 Regulates Contactin 5 to Pattern Dendrites of a Mammalian Retinal Ganglion Cell.","volume":"95","author":"Peng","year":"2017","journal-title":"Neuron"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e93274","DOI":"10.1371\/journal.pone.0093274","article-title":"Melanopsin Ganglion Cells Are the Most Resistant Retinal Ganglion Cell Type to Axonal Injury in the Rat Retina.","volume":"9","author":"P\u00e9rez De Sevilla M\u00fcller","year":"2014","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/cne","article-title":"Displaced Amacrine Cells of the Mouse.","volume":"505","author":"P\u00e9rez De Sevilla M\u00fcller","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.exer.2010.07.012","article-title":"Evaluation of functional integrity of the retinohypothalamic tract in advanced glaucoma using multifocal electroretinography and light-induced melatonin suppression.","volume":"91","author":"P\u00e9rez-Rico","year":"2010","journal-title":"Exp. Eye Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1002\/dvg.22417","article-title":"Generation and characterization of a tamoxifen-inducible EomesCreER mouse line.","volume":"51","author":"Pimeisl","year":"2013","journal-title":"Genesis"},{"key":"B36","first-page":"2213","article-title":"Melanopsin (Opn4) Requirement for Normal Light-Induced Circadian Phase Shifting.","volume":"298","author":"Provencio","year":"","journal-title":"Science"},{"key":"B37","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/415493a","article-title":"Photoreceptive net in the mammalian retina.","volume":"415","author":"Provencio","year":"","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1523\/jneurosci.20-02-00600.2000","article-title":"A novel human opsin in the inner retina.","volume":"20","author":"Provencio","year":"2000","journal-title":"J. Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/cne.24556","article-title":"The M6 cell: a small-field bistratified photosensitive retinal ganglion cell.","volume":"527","author":"Quattrochi","year":"2018","journal-title":"J. Comp. Neurol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1038\/s41467-018-05134-3","article-title":"Single cell transcriptome profiling of retinal ganglion cells identifies cellular subtypes.","volume":"9","author":"Rheaume","year":"2018","journal-title":"Nat. Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1016\/j.visres.2004.06.010","article-title":"Axotomized mouse retinal ganglion cells containing melanopsin show enhanced survival, but not enhanced axon regrowth into a peripheral nerve graft.","volume":"44","author":"Robinson","year":"2004","journal-title":"Vis. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1002\/cne.23521","article-title":"The RNA Binding Protein RBPMS is a Selective Marker of Ganglion Cells in the Mammalian Retina.","volume":"522","author":"Rodriguez","year":"2014","journal-title":"J. Comp. Neurol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1126\/science.1076701","article-title":"Role of melanopsin in circadian responses to light.","volume":"298","author":"Ruby","year":"2002","journal-title":"Science"},{"key":"B44","doi-asserted-by":"publisher","first-page":"E3974","DOI":"10.1073\/pnas.1618551114","article-title":"Molecular codes for cell type specification in Brn3 retinal ganglion cells.","volume":"114","author":"Sajgo","year":"2017","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1146\/annurev-neuro-071714-034120","article-title":"The Types of Retinal Ganglion Cells: current Status and Implications for Neuronal Classification.","volume":"38","author":"Sanes","year":"2015","journal-title":"Annu. Rev. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/j.neuron.2014.03.022.A","article-title":"A role for melanopsin in alpha retinal ganglion cells and contrast detection.","volume":"82","author":"Schmidt","year":"2014","journal-title":"Neuron"},{"key":"B47","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1523\/JNEUROSCI.4117-08.2009","article-title":"Functional and morphological differences among intrinsically photosensitive retinal ganglion cells.","volume":"29","author":"Schmidt","year":"2009","journal-title":"J. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/s12031-008-9091-5","article-title":"Suppression of ganglion cell death by PACAP following optic nerve transection in the rat.","volume":"36","author":"Seki","year":"2008","journal-title":"J. Mol. Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"3378","DOI":"10.1093\/cercor\/bhw270","article-title":"The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways.","volume":"27","author":"Sessa","year":"2017","journal-title":"Cereb. Cortex"},{"key":"B50","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.neuron.2018.06.032","article-title":"Melanopsin phototransduction is repurposed by ipRGC subtypes to shape the function of distinct visual circuits - preprint.","volume":"99","author":"Sonoda","year":"2018","journal-title":"Neuron"},{"key":"B51","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1126\/science.aay3152","article-title":"A noncanonical inhibitory circuit dampens behavioral sensitivity to light.","volume":"368","author":"Sonoda","year":"2020","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1471-213X-1-4","article-title":"Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.","volume":"1","author":"Srinivas","year":"2001","journal-title":"BMC Dev. Biol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.neuron.2017.11.030","article-title":"The M5 cell: a color-opponent intrinsically photosensitive retinal ganglion cell","volume":"97","author":"Stabio","year":"2018","journal-title":"Neuron"},{"key":"B54","doi-asserted-by":"publisher","first-page":"5447","DOI":"10.1523\/JNEUROSCI.0035-14.2014","article-title":"Tbr2 Is Required to Generate a Neural Circuit Mediating the Pupillary Light Reflex.","volume":"34","author":"Sweeney","year":"2014","journal-title":"J. Neurosci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1016\/j.neuron.2019.11.006","article-title":"Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes.","volume":"104","author":"Tran","year":"2019","journal-title":"Neuron"},{"key":"B56","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/j.cub.2007.04.058","article-title":"Local Retinal Circuits of Melanopsin-Containing Ganglion Cells Identified by Transsynaptic Viral Tracing.","volume":"17","author":"Viney","year":"2007","journal-title":"Curr. Biol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"e62841","DOI":"10.1371\/journal.pone.0062841","article-title":"Changes in the Circadian Rhythm in Patients with Primary Glaucoma.","volume":"8","author":"Wang","year":"2013","journal-title":"PLoS One"},{"key":"B58","doi-asserted-by":"publisher","first-page":"5177","DOI":"10.1523\/jneurosci.0471-20.2020","article-title":"Mouse Retinal Cell Atlas: molecular Identification of Over Sixty Amacrine Cell Types.","volume":"40","author":"Yan","year":"2020","journal-title":"J. Neurosci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1007\/s12031-018-1203-2","article-title":"Spatiotemporal Expression Changes of PACAP and Its Receptors in Retinal Ganglion Cells After Optic Nerve Crush.","volume":"68","author":"Ye","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"3174","DOI":"10.4049\/jimmunol.1000749","article-title":"T-bet and Eomesodermin Are Required for T Cell-Mediated Antitumor Immune Responses.","volume":"185","author":"Zhu","year":"2010","journal-title":"J. Immunol."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.826590\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T17:09:13Z","timestamp":1648487353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.826590\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,23]]},"references-count":60,"alternative-id":["10.3389\/fncel.2022.826590"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2022.826590","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,23]]},"article-number":"826590"}}