{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T02:20:44Z","timestamp":1782786044962,"version":"3.54.5"},"reference-count":36,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The pineal gland plays a central role in the photoneuroendocrine system and acts as a photosensory organ in lower vertebrates. The orphan nuclear receptor Rev-erb\u03b1 (NR1D1) has previously been shown to be expressed in the pineal and to be regulated with a robust circadian rhythm during zebrafish embryogenesis. This early pineal expression is under the control of the transcription factor Orthodenticle homeobox 5 (Otx5). In this paper, we show that Otx5 regulates the second zfRev-erb\u03b1 promoter, ZfP2. Despite the absence of a classical Otx-binding site within ZfP2, this regulation depends on the integrity of the Otx5 homeodomain. Mapping experiments as well as EMSAs show that this interaction between Otx5 and ZfP2 depends on a noncanonical bipartite Otx-binding site (GANNCTTA and TAAA) that we called pineal expression related element (PERE). We showed that PERE is necessary for pineal expression in vivo by injecting zebrafish embryos with wild type and mutated versions of zfRev-erb\u03b1 promoter fused to green fluorescent protein. Interestingly, PERE is found upstream of other genes expressed in the pineal gland, suggesting that it may play an important role in governing pineal expression. Our data establish that PERE is a novel cis-acting element contributing to pineal-specific gene expression and to Otx target gene regulation.<\/jats:p>","DOI":"10.1210\/me.2007-0170","type":"journal-article","created":{"date-parts":[[2007,9,14]],"date-time":"2007-09-14T01:48:29Z","timestamp":1189734509000},"page":"23-32","source":"Crossref","is-referenced-by-count":8,"title":["OTX5 Regulates Pineal Expression of the Zebrafish REV-ERB\u03b1 through a New DNA Binding Site"],"prefix":"10.1210","volume":"22","author":[{"given":"Shin-ichi","family":"Nishio","sequence":"first","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Kakizawa","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Chatelain","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge\u0301rard","family":"Triqueneaux","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fre\u0301de\u0301ric","family":"Brunet","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Rambaud","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lamonerie","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Laudet","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Lyon, Institut de Ge\u0301nomique Fonctionnelle de Lyon, Unite\u0301 Mixte de Recherche 5242 du Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Institut Fe\u0301de\u0301ratif de Recherche 128 BioSciences Lyon-Gerland, Ecole Normale Supe\u0301rieure de Lyon, 69364 Lyon Cedex 07, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614001685100_R1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0301-0082(98)00078-1","article-title":"Cellular circadian clocks in the pineal.","volume":"58","author":"Falcon","year":"1999","journal-title":"Prog Neurobiol"},{"key":"2020071614001685100_R2","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1152\/jn.1981.46.5.1018","article-title":"Anatomical and physiological characteristics of pineal photoreceptor cell in the larval lamprey, Petromyzon marinus.","volume":"46","author":"Pu","year":"1981","journal-title":"J Neurophysiol"},{"key":"2020071614001685100_R3","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/aja.1001650205","article-title":"Morphology of the pineal complex of the anadromous sea lamprey, Petromyzon marinus L.","volume":"165","author":"Cole","year":"1982","journal-title":"Am J Anat"},{"key":"2020071614001685100_R4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00612489","article-title":"Photoreception in pineal organs of larval and adult lampreys, Lampetra japonica.","volume":"159","author":"Tamotsu","year":"1986","journal-title":"J Comp Physiol"},{"key":"2020071614001685100_R5","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1768-322X.1997.tb01031.x","article-title":"Photic regulation of pineal function. Analogies between retinal and pineal photoreception.","volume":"89","author":"Meissl","year":"1997","journal-title":"Biol Cell"},{"key":"2020071614001685100_R6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0968-4328(99)00081-5","article-title":"Morphology and spectral sensitivities of retinal and extraretinal photoreceptors in freshwater teleosts.","volume":"31","author":"Kusmic","year":"2000","journal-title":"Micron"},{"key":"2020071614001685100_R7","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1073\/pnas.95.4.1876","article-title":"A pineal regulatory element (PIRE) mediates transactivation by the pineal\/retina-specific transcription factor CRX.","volume":"95","author":"Li","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614001685100_R8","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1046\/j.1471-4159.2001.00555.x","article-title":"Transcriptional regulation of the chicken hydroxyindole-O-methyltransferase gene by the cone-rod homeobox-containing protein.","volume":"79","author":"Bernard","year":"2001","journal-title":"J Neurochem"},{"key":"2020071614001685100_R9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mce.2006.03.021","article-title":"Mechanism of pineal-specific gene expression: the role of E-box and photoreceptor conserved elements.","volume":"252","author":"Appelbaum","year":"2006","journal-title":"Mol Cell Endocrinol"},{"key":"2020071614001685100_R10","doi-asserted-by":"crossref","first-page":"15456","DOI":"10.1073\/pnas.232444199","article-title":"Pineal expression-promoting element (PIPE), a cis-acting element, directs pineal-specific gene expression in zebrafish.","volume":"99","author":"Asaoka","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614001685100_R11","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/ng793","article-title":"Otx5 regulates genes that show circadian expression in the zebrafish pineal complex.","volume":"30","author":"Gamse","year":"2002","journal-title":"Nat Genet"},{"key":"2020071614001685100_R12","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/molbev\/msg085","article-title":"The mammalian Crx genes are highly divergent representatives of the Otx5 gene family, a gnathostome orthology class of orthodenticle-related homeogenes involved in the differentiation of retinal photoreceptors and circadian entrainment.","volume":"20","author":"Plouhinec","year":"2003","journal-title":"Mol Biol Evol"},{"key":"2020071614001685100_R13","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1210\/me.2003-0439","article-title":"Zebrafish serotonin-N-acetyltransferase-2 gene regulation: pineal-restrictive downstream module contains a functional E-box and three photoreceptor conserved elements.","volume":"18","author":"Appelbaum","year":"2004","journal-title":"Mol Endocrinol"},{"key":"2020071614001685100_R14","doi-asserted-by":"crossref","first-page":"11544","DOI":"10.1074\/jbc.M412935200","article-title":"Homeobox-clock protein interaction in zebrafish. A shared mechanism for pineal-specific and circadian gene expression.","volume":"280","author":"Appelbaum","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071614001685100_R15","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1126\/science.289.5477.297","article-title":"An inherited functional circadian clock in zebrafish embryos.","volume":"289","author":"Delaunay","year":"2000","journal-title":"Science"},{"key":"2020071614001685100_R16","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1677\/jme.1.01554","article-title":"The orphan receptor Rev-erb\u03b1 gene is a target of the circadian clock pacemaker.","volume":"33","author":"Triqueneaux","year":"2004","journal-title":"J Mol Endocrinol"},{"key":"2020071614001685100_R17","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1677\/JME-06-0063","article-title":"Two differentially active alternative promoters control the expression of zebrafish orphan nuclear receptor gene Rev-erb\u03b1.","volume":"38","author":"Kakizawa","year":"2007","journal-title":"J Mol Endocrinol"},{"key":"2020071614001685100_R18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0925-4773(98)00162-2","article-title":"OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression.","volume":"82","author":"Bobola","year":"1999","journal-title":"Mech Dev"},{"key":"2020071614001685100_R19","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1093\/molbev\/msh200","article-title":"Evolutionary genomics of nuclear receptors: from twenty-five ancestral genes to derived endocrine systems.","volume":"21","author":"Bertrand","year":"2004","journal-title":"Mol Biol Evol"},{"key":"2020071614001685100_R20","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0092-8674(94)90292-5","article-title":"Homeodomain-DNA recognition.","volume":"78","author":"Gehring","year":"1994","journal-title":"Cell"},{"key":"2020071614001685100_R21","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/79951","article-title":"Effective targeted gene \u2018knockdown\u2019 in zebrafish.","volume":"26","author":"Nasevicius","year":"2000","journal-title":"Nat Genet"},{"key":"2020071614001685100_R22","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1002\/j.1460-2075.1990.tb07505.x","article-title":"Protein-DNA contacts in the structure of a homeodomain-DNA complex determined by nuclear magnetic resonance spectroscopy in solution.","volume":"9","author":"Otting","year":"1990","journal-title":"EMBO J"},{"key":"2020071614001685100_R23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0092-8674(94)90231-3","article-title":"Crystal structure of the Oct-1 POU domain bound to an octamer site: DNA recognition with tethered DNA-binding modules.","volume":"77","author":"Klemm","year":"1994","journal-title":"Cell"},{"key":"2020071614001685100_R24","doi-asserted-by":"crossref","first-page":"6886","DOI":"10.1073\/pnas.93.14.6886","article-title":"Conservation and diversification in homeodomain-DNA interactions: a comparative genetic analysis.","volume":"93","author":"Wilson,","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614001685100_R25","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0168-9525(01)02418-0","article-title":"Downstream of Otx2, or how to get a head.","volume":"17","author":"Boncinelli","year":"2001","journal-title":"Trends Genet"},{"key":"2020071614001685100_R26","doi-asserted-by":"crossref","first-page":"7673","DOI":"10.1128\/MCB.20.20.7673-7684.2000","article-title":"Reprogrammable recognition codes in bicoid homeodomain-DNA interaction.","volume":"20","author":"Dave","year":"2000","journal-title":"Mol Cell Biol"},{"key":"2020071614001685100_R27","doi-asserted-by":"crossref","first-page":"8112","DOI":"10.1128\/MCB.20.21.8112-8123.2000","article-title":"Target selectivity of bicoid is dependent on nonconsensus site recognition and protein-protein interaction.","volume":"20","author":"Zhao","year":"2000","journal-title":"Mol Cell Biol"},{"key":"2020071614001685100_R28","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0896-6273(01)80045-3","article-title":"floating head and masterblind regulate neuronal patterning in the roof of the forebrain.","volume":"18","author":"Masai","year":"1997","journal-title":"Neuron"},{"key":"2020071614001685100_R29","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/S0896-6273(00)80394-3","article-title":"Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes.","volume":"19","author":"Chen","year":"1997","journal-title":"Neuron"},{"key":"2020071614001685100_R30","doi-asserted-by":"crossref","first-page":"28549","DOI":"10.1074\/jbc.271.45.28549","article-title":"Ret 4, a positive acting rhodopsin regulatory element identified using a bovine retina in vitro transcription system.","volume":"271","author":"Chen","year":"1996","journal-title":"J Biol Chem"},{"key":"2020071614001685100_R31","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s101269900014","article-title":"GFP as a genetic marker scorable throughout the life cycle of transgenic zebra fish.","volume":"2","author":"Gibbs","year":"2000","journal-title":"Mar Biotechnol (NY)"},{"key":"2020071614001685100_R32","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1098\/rstb.2003.1303","article-title":"Evolution of photosensory pineal organs in new light: the fate of neuroendocrine photoreceptors.","volume":"358","author":"Ekstrom","year":"2003","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"2020071614001685100_R33","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/70591","article-title":"Retinopathy and attenuated circadian entrainment in Crx-deficient mice.","volume":"23","author":"Furukawa","year":"1999","journal-title":"Nat Genet"},{"key":"2020071614001685100_R34","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/nn1155","article-title":"Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development.","volume":"6","author":"Nishida","year":"2003","journal-title":"Nat Neurosci"},{"key":"2020071614001685100_R35","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1007\/s00109-006-0048-2","article-title":"Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants.","volume":"84","author":"Chatelain","year":"2006","journal-title":"J Mol Med"},{"key":"2020071614001685100_R36","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0091-679X(04)77027-2","article-title":"Spatial and temporal expression of the zebrafish genome by large-scale in situ hybridization screening.","volume":"77","author":"Thisse","year":"2004","journal-title":"Methods Cell Biol"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/22\/1\/23\/8936856\/mend0023.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/22\/1\/23\/8936856\/mend0023.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T01:09:54Z","timestamp":1594948194000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/22\/1\/23\/2683985"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,1,1]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2008,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2007-0170","relation":{},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,1,1]]}}}