{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:14:52Z","timestamp":1787015692356,"version":"build-2736575974"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,4,6]],"date-time":"2018-04-06T00:00:00Z","timestamp":1522972800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31430083"],"award-info":[{"award-number":["31430083"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31772692"],"award-info":[{"award-number":["31772692"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Melatonin is a key hormone that regulates circadian rhythms, metabolism, and reproduction. However, the mechanisms of melatonin synthesis and secretion have not been fully defined. The purpose of this study was to investigate the functions of the\n                    <jats:styled-content style=\"fixed-case\">LIM<\/jats:styled-content>\n                    homeobox transcription factor Isl1 in regulating melatonin synthesis and secretion in porcine pineal gland. We found that Isl1 is highly expressed in the melatonin\u2010producing cells in the porcine pineal gland. Further functional studies demonstrate that Isl1 knockdown in cultured primary porcine pinealocytes results in the decline of melatonin and arylalkylamine N\u2010acetyltransferase (\n                    <jats:styled-content style=\"fixed-case\">AANAT<\/jats:styled-content>\n                    )\n                    <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n                    levels by 29.2% and 72.2%, respectively, whereas Isl1 overexpression raised by 1.3\u2010fold and 2.7\u2010fold. In addition, the enhancing effect of norepinephrine (\n                    <jats:styled-content style=\"fixed-case\">NE<\/jats:styled-content>\n                    ) on melatonin synthesis was abolished by Isl1 knockdown. The in vivo intracerebroventricular\n                    <jats:styled-content style=\"fixed-case\">NE<\/jats:styled-content>\n                    injections upregulate Isl1\n                    <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n                    and protein levels by about threefold and 4.5\u2010fold in the porcine pineal gland. We then examined the changes in Isl1 expression in the pineal gland and global melatonin levels throughout the day. The results show that Isl1 protein level at 24:00 is 2.5\u2010fold higher than that at 12:00, which is parallel to melatonin levels. We further found that Isl1 increases the activity of\n                    <jats:styled-content style=\"fixed-case\">AANAT<\/jats:styled-content>\n                    promoter, and the effect of\n                    <jats:styled-content style=\"fixed-case\">NE<\/jats:styled-content>\n                    on Isl1 expression was blocked by an\n                    <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n                    inhibitor. Collectively, the results presented here demonstrate that Isl1 positively modulates melatonin synthesis by targeting\n                    <jats:styled-content style=\"fixed-case\">AANAT<\/jats:styled-content>\n                    , via the\n                    <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n                    signaling pathway of\n                    <jats:styled-content style=\"fixed-case\">NE<\/jats:styled-content>\n                    . These suggest that Isl1 plays important roles in maintaining the daily circadian rhythm.\n                  <\/jats:p>","DOI":"10.1111\/jpi.12481","type":"journal-article","created":{"date-parts":[[2018,2,26]],"date-time":"2018-02-26T10:32:10Z","timestamp":1519641130000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["<scp>LIM<\/scp>\n                    homeobox transcription factor Isl1 is required for melatonin synthesis in the pig pineal gland"],"prefix":"10.1111","volume":"65","author":[{"given":"Jinglin","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Agrobiotechnology College of Biological Sciences China Agricultural University  Beijing China"},{"name":"College of Veterinary Medicine Yangzhou University  Yangzhou, Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtao","family":"Qiu","sequence":"additional","affiliation":[{"name":"State Key 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