{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:15:57Z","timestamp":1787015757762,"version":"build-2736575974"},"reference-count":58,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Melatonin is synthesized in the pineal gland during nighttime in response to nocturnal increase in the activity of the enzyme aralkylamine\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyltransferase (AANAT), the transcription of which is modulated by several homeodomain transcription factors. Recent work suggests that the homeodomain transcription factor ISL LIM homeobox 2 (ISL2) is expressed in the pineal gland, but its role is currently unknown. With the purpose of identifying the mechanisms that control pineal expression of\n                    <jats:italic>Isl2<\/jats:italic>\n                    and the possible function of\n                    <jats:italic>Isl2<\/jats:italic>\n                    in circadian pineal biology, we report that\n                    <jats:italic>Isl2<\/jats:italic>\n                    is specifically expressed in the pinealocytes of the rat pineal gland. Its expression exhibits a 24\u2009h rhythm with high transcript and protein levels during the day and a trough in the second half of the night. This rhythm persists in darkness, and lesion studies reveal that it requires intact function of the suprachiasmatic nuclei, suggesting intrinsic circadian regulation. In vivo and in vitro experiments show that pineal\n                    <jats:italic>Isl2<\/jats:italic>\n                    expression is repressed by adrenergic signaling acting via cyclic AMP; further,\n                    <jats:italic>Isl2<\/jats:italic>\n                    is negatively regulated by the nocturnal transcription factor cone\u2010rod homeobox. During development, pineal\n                    <jats:italic>Isl2<\/jats:italic>\n                    expression is detectable from embryonic day 19, preceding\n                    <jats:italic>Aanat<\/jats:italic>\n                    by several days. In vitro knockdown of\n                    <jats:italic>Isl2<\/jats:italic>\n                    is accompanied by an increase in\n                    <jats:italic>Aanat<\/jats:italic>\n                    transcript levels suggesting that ISL2 represses its daytime expression. Thus, rhythmic expression of ISL2 in pinealocytes is under the control of the suprachiasmatic nucleus acting via adrenergic signaling in the gland to repress nocturnal expression, while ISL2 itself negatively regulates daytime pineal expression of\n                    <jats:italic>Aanat<\/jats:italic>\n                    and thereby suggestively enhances the circadian rhythm in melatonin synthesis.\n                  <\/jats:p>","DOI":"10.1111\/jpi.12905","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T01:06:47Z","timestamp":1693444007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The ISL LIM\u2010homeobox 2 transcription factor is negatively regulated by circadian adrenergic signaling to repress the expression of\n                    <i>Aanat<\/i>\n                    in pinealocytes of the rat pineal gland"],"prefix":"10.1111","volume":"75","author":[{"given":"Kuno 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