{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:58:58Z","timestamp":1782280738426,"version":"3.54.5"},"posted":{"date-parts":[[2025,5,1]]},"group-title":"Developmental Biology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["EY024376"],"award-info":[{"award-number":["EY024376"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["EY032898"],"award-info":[{"award-number":["EY032898"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["EY034219"],"award-info":[{"award-number":["EY034219"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["P30EY028102"],"award-info":[{"award-number":["P30EY028102"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"NIDCR","doi-asserted-by":"crossref","award":["DE028527"],"award-info":[{"award-number":["DE028527"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"NIDCR","doi-asserted-by":"crossref","award":["DE026433"],"award-info":[{"award-number":["DE026433"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000072","name":"NIDCR","doi-asserted-by":"crossref","award":["T90DE023520"],"award-info":[{"award-number":["T90DE023520"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,1]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  The intrinsically photosensitive retinal ganglion cells (ipRGC) are the conduit between the retinas and brain regions responsible for non-image-forming and image-forming vision. In mice, six ipRGC subtypes have been discovered based on morphological characteristics, functions, and molecular profiles. All ipRGCs arise from Tbr2-expressing RGCs during developmental stages and subsequently diverge and differentiate into the six mature, distinct subtypes in adult retinas. However, the cellular and molecular mechanisms controlling the formation and maturation of the six ipRGC subtypes remain elusive. Here, we demonstrate that two\n                  <jats:italic>Tbr2<\/jats:italic>\n                  -dependent transcription factors,\n                  <jats:italic>Iroquois-related homeobox 1<\/jats:italic>\n                  (\n                  <jats:italic>Irx1<\/jats:italic>\n                  ) and\n                  <jats:italic>T-box containing factor 20<\/jats:italic>\n                  (\n                  <jats:italic>Tbx20<\/jats:italic>\n                  ), are key downstream transcription factors guiding lineage segregations of Tbr2-expressing RGC into distinct adult ipRGC subtypes. Both factors also control\n                  <jats:italic>Opn4<\/jats:italic>\n                  expression.\n                  <jats:italic>Irx1<\/jats:italic>\n                  is expressed in the M3, M4, and M5 subtypes, while\n                  <jats:italic>Tbx20<\/jats:italic>\n                  is predominantly expressed in M1, M2, M6, and subgroups of M3 and M5. When\n                  <jats:italic>Irx1<\/jats:italic>\n                  is ablated during retinal development,\n                  <jats:italic>Opn4<\/jats:italic>\n                  expression is significantly reduced in the M3, M4, and M5 ipRGC groups; however, the formation of\n                  <jats:italic>Irx1<\/jats:italic>\n                  -expressing ipRGCs is not affected. In contrast, when\n                  <jats:italic>Tbx20<\/jats:italic>\n                  is deleted, a significant number of\n                  <jats:italic>Tbx20<\/jats:italic>\n                  -expressing cells fail to develop while\n                  <jats:italic>Opn4<\/jats:italic>\n                  expression is down-regulated. These findings reveal two parallel transcription cascades downstream of Tbr2 for controlling ipRGC subtype formation, fate divergence, and maintenance in the adult retina.\n                <\/jats:p>","DOI":"10.1101\/2025.04.29.651262","type":"posted-content","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T04:50:11Z","timestamp":1746075011000},"source":"Crossref","is-referenced-by-count":1,"title":["Tbr2-Dependent Parallel Pathways Regulate the Development of Distinct ipRGC Subtypes"],"prefix":"10.64898","author":[{"given":"Takae","family":"Kiyama","sequence":"first","affiliation":[{"name":"Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Kang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halit Y.","family":"Altay","sequence":"additional","affiliation":[{"name":"Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jiun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leviette","family":"Sigala","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Eliason","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6524-1006","authenticated-orcid":false,"given":"Brad A.","family":"Amendt","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9700-6964","authenticated-orcid":false,"given":"Chai-An","family":"Mao","sequence":"additional","affiliation":[{"name":"Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA"},{"name":"The MD 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