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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits
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A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

机译：旁分泌信号的多样性维持了视交叉上核回路中的分子昼夜节律循环

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摘要

The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker of mammals, coordinating daily rhythms of behavior and metabolism. Circadian timekeeping in SCN neurons revolves around transcriptional/posttranslational feedback loops, in which Period (Per) and Cryptochrome (Cry) genes are negatively regulated by their protein products. Recent studies have revealed, however, that these "core loops" also rely upon cytosolic and circuit-level properties for sustained oscillation. To characterize interneuronal signals responsible for robust pacemaking in SCN cells and circuits, we have developed a unique coculture technique using wild-type (WT) "graft" SCN to drive pacemaking (reported by PER2::LUCIFER-ASE bioluminescence) in "host" SCN deficient either in elements of neuropeptidergic signaling or in elements of the core feedback loop. We demonstrate that paracrine signaling is sufficient to restore cellular synchrony and amplitude of pacemaking in SCN circuits lacking vasoactive intestinal peptide (VIP). By using grafts with mutant circadian periods we show that pacemaking in the host SCN is specified by the genotype of the graft, confirming graft-derived factors as determinants of the host rhythm. By combining pharmacological with genetic manipulations, we show that a hierarchy of neuropeptidergic signals underpins this paracrine regulation, with a preeminent role for VIP augmented by contributions from arginine vasopressin (AVP) and gastrin-releasing peptide (GRP). Finally, we show that interneuronal signaling is sufficiently powerful to maintain circadian pacemaking in arrhythmic Cry-null SCN, deficient in essential elements of the transcriptional negative feedback loops. Thus, a hierarchy of paracrine neuropeptidergic signals determines cell- and circuit-level circadian pacemaking in the SCN.
机译：视交叉上核（SCN）是哺乳动物的主要昼夜节律起搏器，负责协调行为和新陈代谢的日常节律。 SCN神经元的昼夜节律围绕着转录/翻译后反馈环而进行，在该环中，Period（Per）和Cryptochrome（Cry）基因受到蛋白质产物的负调控。但是，最近的研究表明，这些“核心环”还依赖于胞质和电路水平的特性来持续振荡。为了表征负责SCN细胞和电路中强劲起搏的神经元间信号，我们开发了一种独特的共培养技术，该技术使用野生型（WT）“移植” SCN来驱动“宿主”中的起搏（由PER2 :: LUCIFER-ASE生物发光报告）。 SCN在神经肽能信号传导元件或核心反馈回路元件中均不足。我们证明旁分泌信号足以恢复缺乏血管活性肠肽（VIP）的SCN电路中的细胞同步性和起搏幅度。通过使用具有昼夜节律周期突变的移植物，我们表明宿主SCN中的起搏是由移植物的基因型指定的，从而证实了源自移植物的因子是宿主节律的决定因素。通过将药理学和基因操作相结合，我们显示出神经肽能信号的层次支撑了这种旁分泌调节，VIP的主要作用是精氨酸加压素（AVP）和胃泌素释放肽（GRP）的贡献。最后，我们表明神经元间信号传导足够强大，可以在心律不齐的Cry-null SCN中维持昼夜节律起搏，而转录负反馈环的基本要素不足。因此，旁分泌神经肽能信号的层次决定了SCN中细胞和电路水平的昼夜节律起搏。

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    Elizabeth S. Maywood; Johanna E. Chesham; John A. OBrien; Michael H. Hastings;

  • 作者单位

    Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;

    Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;

    Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;

    Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    organotypic slice; VPAC2; BB2r;

    机译：器官切片VPAC2;BB2r;

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