{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:51:16Z","timestamp":1760147476004,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research to K.S.","award":["No. 17K01954","No. 20K05725"],"award-info":[{"award-number":["No. 17K01954","No. 20K05725"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In contrast to the case in mammals, the fish optic nerve can spontaneously regenerate and visual function can be fully restored 3\u20134 months after optic nerve injury (ONI). However, the regenerative mechanism behind this has remained unknown. This long process is reminiscent of the normal development of the visual system from immature neural cells to mature neurons. Here, we focused on the expression of three Yamanaka factors (Oct4, Sox2, and Klf4: OSK), which are well-known inducers of induced pluripotent stem (iPS) cells in the zebrafish retina after ONI. mRNA expression of OSK was rapidly induced in the retinal ganglion cells (RGCs) 1\u20133 h after ONI. Heat shock factor 1 (HSF1) mRNA was most rapidly induced in the RGCs at 0.5 h. The activation of OSK mRNA was completely suppressed by the intraocular injection of HSF1 morpholino prior to ONI. Furthermore, the chromatin immunoprecipitation assay showed the enrichment of OSK genomic DNA bound to HSF1. The present study clearly showed that the rapid activation of Yamanaka factors in the zebrafish retina was regulated by HSF1, and this sequential activation of HSF1 and OSK might provide a key to unlocking the regenerative mechanism of injured RGCs in fish.<\/jats:p>","DOI":"10.3390\/ijms24043253","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:01:45Z","timestamp":1675825305000},"page":"3253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Specific Activation of Yamanaka Factors via HSF1 Signaling in the Early Stage of Zebrafish Optic Nerve Regeneration"],"prefix":"10.3390","volume":"24","author":[{"given":"Kayo","family":"Sugitani","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Mokuya","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuichi","family":"Homma","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minami","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayano","family":"Konno","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3462-9320","authenticated-orcid":false,"given":"Kazuhiro","family":"Ogai","sequence":"additional","affiliation":[{"name":"AI Hospital\/Macro Signal Dynamics Research and Development Center, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1126\/science.aal5060","article-title":"Regenerating optic pathways from the eye to the brain","volume":"356","author":"Laha","year":"2017","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1146\/annurev-vision-022720-094953","article-title":"Axon Regeneration in the Mammalian Optic Nerve","volume":"6","author":"Williams","year":"2020","journal-title":"Annu. Rev. Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.21037\/atm-20-5351","article-title":"The basic science of optic nerve regeneration","volume":"15","author":"Fague","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/0014-4886(63)90093-1","article-title":"Preferential selection of central pathways by regenerating optic fibers","volume":"7","author":"Attardi","year":"1963","journal-title":"Exp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1086\/physzool.21.4.30152014","article-title":"Patterning of central synapses in regeneration of the optic nerve in teleosts","volume":"21","author":"Sperry","year":"1948","journal-title":"Physiol. Zool."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.conb.2014.03.019","article-title":"Axonal regeneration in zebrafish","volume":"27","author":"Becker","year":"2014","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.preteyeres.2013.12.007","article-title":"M\u00fcller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish","volume":"40","author":"Lenkowski","year":"2014","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nrn3723","article-title":"M\u00fcller glial cell reprogramming and retina regeneration","volume":"15","author":"Goldman","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"dev167692","DOI":"10.1242\/dev.167692","article-title":"Model systems for regeneration: Zebrafish","volume":"146","author":"Marques","year":"2019","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/0-387-32442-9_73","article-title":"Upregulation of transglutaminase in the goldfish retina during optic nerve regeneration","volume":"Volume 572","author":"Sugitani","year":"2006","journal-title":"Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.neures.2008.03.008","article-title":"Changes of phospho-growth associated protein 43 (phospho-GAP43) in zebrafish retina after optic nerve injury: A long term observation","volume":"61","author":"Kaneda","year":"2008","journal-title":"Neurosci. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/978-3-319-75402-4_48","article-title":"Alternative Splicing for Activation of Coagulation Factor XIII-A in the Fish Retina After Optic Nerve Injury","volume":"1074","author":"Sugitani","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.neuroscience.2006.07.042","article-title":"Upregulation of retinal transglutaminase during the axonal elongation stage of goldfish optic nerve regeneration","volume":"142","author":"Sugitani","year":"2006","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1111\/j.1471-4159.2009.06182.x","article-title":"Nitric oxide-cGMP signaling regulates axonal elongation during optic nerve regeneration in the goldfish in vitro and in vivo","volume":"110","author":"Koriyama","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.neuint.2012.06.004","article-title":"A distinct effect of transient and sustained upregulation of cellular factor XIII in the goldfish retina and optic nerve on optic nerve regeneration","volume":"61","author":"Sugitani","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0306-4522(99)00202-X","article-title":"Fast and slow recovery phases of goldfish behavior after transection of the optic nerve revealed by a computer image processing system","volume":"93","author":"Kato","year":"1999","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.neuint.2012.08.015","article-title":"Upregulation of anti-apoptotic factors in upper motor neurons after spinal cord injury in adult zebrafish","volume":"61","author":"Ogai","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.neuint.2007.01.012","article-title":"Upregulation of IGF-I in the goldfish retinal ganglion cells during the early stage of optic nerve regeneration","volume":"50","author":"Koriyama","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8346","DOI":"10.1523\/JNEUROSCI.1809-04.2004","article-title":"Role of purpurin as a retinol-binding protein in goldfish retina during the early stage of optic nerve regeneration: Its priming action on neurite outgrowth","volume":"24","author":"Matsukawa","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/978-3-319-17121-0_89","article-title":"A Possible Role of Neuroglobin in the Retina After Optic Nerve Injury: A Comparative Study of Zebrafish and Mouse Retina","volume":"854","author":"Sugitani","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.bbrc.2017.09.127","article-title":"A novel function of neuroglobin for neuroregeneration in mice after optic nerve injury","volume":"493","author":"Sugitani","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.neuint.2011.02.017","article-title":"HSP70, the earliest-induced gene in the zebrafish retina during optic nerve regeneration: Its role in cell survival","volume":"58","author":"Nagashima","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/978-1-4614-0631-0_84","article-title":"HSP 70 gene expression in the zebrafish retina after optic nerve injury: A comparative study under heat shock stresses","volume":"723","author":"Fujikawa","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.preteyeres.2013.07.004","article-title":"A molecular mechanism of optic nerve regeneration in fish: The retinoid signaling pathway","volume":"37","author":"Kato","year":"2013","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.cell.2014.12.016","article-title":"Reduced expression of MYC increases longevity and enhances healthspan","volume":"160","author":"Hofmann","year":"2015","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nbt1374","article-title":"Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts","volume":"26","author":"Nakagawa","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.stem.2007.12.001","article-title":"c-Myc is dispensable for direct reprogramming of mouse fibroblasts","volume":"2","author":"Wernig","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1096\/fj00-0294rev","article-title":"Roles of the heat shock transcription factors in regulation of the heat shock response and beyond","volume":"15","author":"Pirkkala","year":"2001","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/ng2012","article-title":"Genetic reconstruction of a functional transcriptional regulatory network","volume":"39","author":"Hu","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nrm2938","article-title":"Heat shock factors: Integrators of cell stress, development and lifespan","volume":"11","author":"Akerfelt","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.1111\/j.1742-4658.2010.07827.x","article-title":"The heat shock factor family and adaptation to proteotoxic stress","volume":"277","author":"Fujimoto","year":"2010","journal-title":"FEBS J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1146\/annurev-biochem-060809-095203","article-title":"Regulation of HSF1 function in the heat stress response: Implications in aging and disease","volume":"80","author":"Anckar","year":"2011","journal-title":"Annu. Rev. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1242\/jcs.132605","article-title":"HSF1 at a glance","volume":"127","author":"Vihervaara","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1167\/iovs.18-26216","article-title":"Neuroprotective Effects of HSF1 in Retinal Ischemia-Reperfusion Injury","volume":"60","author":"Liu","year":"2019","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.tins.2005.03.003","article-title":"SOX2 functions in adult neural stem cells","volume":"28","author":"Episkopou","year":"2005","journal-title":"Trends Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"579","DOI":"10.5966\/sctm.2012-0179","article-title":"Concise review: The involvement of SOX2 in direct reprogramming of induced neural stem\/precursor cells","volume":"2","author":"Maucksch","year":"2013","journal-title":"Stem Cells Transl. Med."},{"key":"ref_39","first-page":"1936","article-title":"SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis","volume":"112","author":"Cimadamore","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/0306-4522(89)90295-9","article-title":"Quantitative electrophysiological studies of regenerating visuotopic maps in goldfish-II. Delayed recovery of sensitivity to small light flashes","volume":"32","author":"Northmore","year":"1989","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/0014-4886(69)90124-1","article-title":"Changes in the morphology and amino acid incorporation of regenerating goldfish optic neurons","volume":"23","author":"Murray","year":"1969","journal-title":"Exp. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0168-0102(00)00131-0","article-title":"Slow recovery of goldfish retinal ganglion cells\u2019 soma size during regeneration","volume":"37","author":"Devadas","year":"2000","journal-title":"Neurosci. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41586-020-2975-4","article-title":"Reprogramming to recover youthful epigenetic information and restore vision","volume":"88","author":"Lu","year":"2020","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:26:27Z","timestamp":1760120787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,7]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043253"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043253","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,2,7]]}}}