Chronobiology—2017 Nobel Prize in Physiology or Medicine
Li Yuan, Yirou Li, Xiaodong XuHebei Normal University, College of Life Sciences, Shijiazhuang 050024, China第一联系人:
收稿日期:2017-12-4修回日期:2017-12-22网络出版日期:--
| 基金资助: |
Received:2017-12-4Revised:2017-12-22Online:--
| Fund supported: |
摘要
关键词：
Abstract
Keywords：
PDF (672KB)元数据多维度评价相关文章导出EndNote|Ris|Bibtex收藏本文
本文引用格式
袁力, 李艺柔, 徐小冬. 时间生物学—2017年诺贝尔生理或医学奖解读. 遗传[J], 2018, 40(1): 1-11 doi:10.16288/j.yczz.17-397
Li Yuan, Yirou Li, Xiaodong Xu.
2017年度的诺贝尔生理或医学奖颁给了3位美国科学家(Michael W. Young、Jeffrey C. Hall和Michael Rosbash),以表彰他们在发现果蝇(Drosophila melanogaster)生物钟基因及分子调控机制过程中的重要贡献。此次颁奖也使得生物节律和时间生物学研究领域的诸多科学问题再次引起人们的广泛关注。
太古至今,承载着众多生命的地球在自转的同时还在围绕着太阳公转,导致光照、温度、潮汐、养分和湿度等环境因素均呈现出明显的周期性变化,这些周期性变化的环境因子极大地影响着地球上生物体生长发育和新陈代谢的过程。在漫长的进化历程中,生物体通过调整机体内的生理生化过程以及自身的行为等来适应环境信号的周期性变化,进而增强其种群的生存和竞争能力。生物体表现出的这种周期性变化的特征被称为生物节律(biological rhythms)。生物体内进化出的感知环境信号和调控生物节律周期性产生的内源分子机器被称为生物钟(biological clock)。研究生物节律现象、调控机制及其应用的学科被称为“时间生物学”(chronobiology)。时间生物学领域最主要的研究对象是内源性近24 h周期长度的节律现象,也被称为近日节律(circadian rhythms)。本文将概括自然界中生物节律现象的发现及遗传学研究基础,阐述生物钟调控的近日节律相关理论体系的确立,并结合3位获得2017年诺贝尔生理或医学奖科学家的贡献对果蝇及其他物种中分子机制的研究成果以及当前时间生物学领域的研究和应用前景展开介绍。
1 生物节律现象的发现
1729年,法国天文学家Jean Jacques d’Ortous de Mairan完成了第一个有文字记载的生物节律实验：在自然条件下含羞草(Mimosa pudica)的羽状复叶在白天打开、在夜间向下合拢,de Mairan发现在持续黑暗条件下含羞草叶片依然保持与昼夜一致的节律性运动[1]。该结果证明,在恒定条件下依然维持周期节律运转的调控来自机体内部的作用机制,即内源的生物钟(internal biological clock)。1758年,法国科学家Henri-Louis Duhamel du Monceau为了排除de Mairan实验中可能存在光泄漏、温度波动等的干扰,利用含羞草在黑暗的酒窖中和持续较高温度的环境中进行了更严格的实验,结果证实叶片在恒定条件下保持既定的周期节律性运动并不依赖于环境中的光照和温度条件[2]。在实验过程中,他还发现如果在下午给予在黑暗环境中生长的含羞草照射阳光,叶片在后续的夜间合拢的时间被推迟,即节律出现了延迟现象;人们后续的研究证实该实验中的光信号处理可“重置”既定的周期节律 (light resetting)。1832年,瑞士植物学家 Augustus Pyramus de Candolle在持续黑暗或持续光照条件下(温度和湿度恒定)检测含羞草叶片节律性运动,发现在黑暗条件下叶片节律性运动的周期接近24 h,而在持续光照条件下周期约为22 h;他还发现人为设定的光暗组合可以重新驯化叶片运动的周期节律并使之与环境光周期同步化(synchronization)[3]。著名植物学家林奈(Carolus Linnaeus)发现不同物种的花瓣在一天当中特定时间开放和闭合,并在1751年根据此现象用多种花卉绘制了著名的花钟(floral clock或horologium florae)(图1)。1922年,美国科学家Curt Paul Richter发现大鼠一天的运动节律现象同样是由自身内源生物钟控制的[4],1968年发现失明的猴子在环境恒定的条件下依然可以精准地维持自身的运动-休息的节律性[5];同一研究阶段的其他科学家也陆续报道了果蝇、蜜蜂(Apis mellifera)、鸡(Gallus gallu)和蜥蜴(Podarcis sicula)等多个物种均存在显著的昼夜节律现象[6]。从18世纪至20世纪中叶,科学家的实验结果均证实,动植物的周期近24 h的节律现象是由不依赖外界环境变化的内源性机制所调控。1959年,美国明尼苏达大学著名生理学家Franz Halberg提出用“circadian clock”一词来定义调控周期近24 h节律的生物钟以及用“chronobiology”一词定义时间生物学,并用毕生的工作推动时间生物学领域的建立和在生理医学领域的应用研究。
如果将自然界中的生物节律从广义上进行归类,包括近日节律、潮汐节律、月节律、季节节律和年节律。如果以节律振荡的周期长度来归类,包括小于24 h的超日节律(ultradian rhythms,如间歇性激素分泌、人类异相睡眠等)、近24 h的近日节律(circadian rhythms,如研究最为广泛的昼夜节律)、长于28小时的亚日节律(infradian rhythms,如人类的月节律——月经周期,鸟类的迁徙和动物冬眠等季节节律或年节律等)等。
图1
新窗口打开|下载原图ZIP|生成PPT图1林奈绘制的花钟
200年前植物学家林奈发现不同物种的植物的花瓣在一天中不同的时段开放和闭合,并据此绘制了此图的花钟。
Fig. 1Carolus Linnaeus's floral clock
2 生物钟可遗传性探索及时间生物学理论研究体系的建立
20世纪是遗传学迅速发展的时期。德国生物学家Erwin Bünning在20世纪30年代将节律周期分别为23 h和26 h的两种多花菜豆(Phaseolus multiflorus)进行杂交,发现F1代植株的节律周期主要分布于两个亲本之间( 约为25 h左右),而F2代群体中分离出现了部分与亲本周期相似的植株[6]。该结果首次证明内源生物钟调控的近日节律性状是可以独立遗传的,该研究结果初步确立了生物节律的遗传学基础(图2)。1948年,德国生物学家Von Richard Pohl检测到眼虫(Euglena gracilis)趋光敏感性受到生物钟调控,确定了生物节律可以是单细胞水平上的特征[7]。1954年,英裔美国科学家Colin Pittendrigh发现,生活在持续黑暗,但温度分别为16、21和26℃ 3种条件下的果蝇羽化的周期均维持在24 h左右[8],即在一个较为宽泛的温度范围内,生物钟周期长度具有“温度补偿”(temperature compensation)的特性,这一发现对于理解变温动物及植物的季节性环境适应性十分关键。此外,他们的研究工作还完善了生物节律如何响应环境信号的相位响应曲线(phase response curve, PRC)的实验方法和理论模型(图3),在生物钟的驯化(entrainment,指环境中周期性变化的信号作为授时因子使得生物钟及节律性在周期和相位上与之同步)机制相关研究中做出了重要贡献[9]。
图2
新窗口打开|下载原图ZIP|生成PPT图2时间生物学研究历史事件表
对时间生物学领域开创性的研究工作以时间为序进行初步归纳,限于篇幅和文献限制只列出了其中一部分的重要事件。
Fig. 2The milestones of the chronohistory
图3
新窗口打开|下载原图ZIP|生成PPT图3生物节律可对环境信号做出响应
环境中诸多信号如光、温度等可引起节律振荡曲线的后置或前移,表明生物钟可对该环境信号做出响应。当外界信号瞬时处理的时间出现在既定曲线的峰值之前时,节律性振荡的峰值出现时间将滞后(A上);当信号瞬时处理在峰值出现之后的时间点时,通常会引起后续节律性振荡的曲线整体前移(A下)。根据在一天中不同时刻处理的信号(如光、温度等)所引起的峰值相位迁移情况而绘制的相位响应曲线(B),图示中包括相位前置、相位不响应区段、相位后移,以及该类响应曲线中标志性的折点(相位延迟最大的时间点与相位前置最大的时间点之间的相应区段,用虚线连接)。
Fig. 3Circadian rhythm response to environmental cues
1958年,美国皮肤科医生Aaron Lerner和他的研究团队从牛的松果体提取物中分离得到一种可以漂白青蛙皮肤的吲哚类化合物,将之命名为“褪黑激素(Melatonin)”[10]。Lerner服用了100 mg褪黑激素之后发现除了感觉困倦之外没有其他不良反应。后来的研究证实褪黑激素是调控哺乳动物昼夜节律尤其是“睡眠-觉醒”节律(sleep-wake rhythm)的关键激素。视网膜感光细胞通过视交叉上核将光信号传递至松果体抑制褪黑激素在白天的合成,从而保证白天机体的警觉性。褪黑激素的合成受生物钟调控,其浓度在恒定环境条件下依然能维持近24 h的昼夜节律,即褪黑激素主要在傍晚开始合成并在夜间累积为最大值,白天机体内该激素的浓度达到最低值[11]。鉴于科学家们对动植物生理水平上昼夜节律的突破性研究进展,1960年冷泉港定量生物学研讨会上开设了“生物钟专场”,对生物节律相关研究进展进行介绍,标志着时间生物学作为一个新兴研究领域的开端。
1962年,德国生物学家Jürgen Aschoff和Rütger Wever开展了对人体昼夜节律的调控机理进行系统研究。他们第一次将志愿者(包括Aschoff本人)隔离在没有任何计时设备的恒定环境条件中,通过对多项生理指标的持续检测,发现在与外界环境隔离之后,人的睡眠、体温、排尿量、尿液中钾离子和钙离子的浓度均维持稳定的昼夜节律性,周期略长于24 h[12]。在随后的研究中,Aschoff和Wever发现部分志愿者体温、排尿量的节律与睡眠节律出现不同步的现象[13],暗示着人体可能存在不止一种生物节律的调控机制。
环境中多种信号,例如光、温度、进食等可以作为授时因子(time giver)调节机体的昼夜节律相位。1965年,Aschoff及其合作者观测到苍头燕雀(Fringilla coelebs)及人(Homo sapiens)的运动行为节律周期的长度随光强增加而缩短的现象(被称之为“Aschoff法则”,即“Aschoff’s Rule”)[14],该现象后续在多个物种被证实存在,并据此建立了时间生物学领域研究周期节律是否响应环境光信号的光强响应曲线(fluence response curve, FRC)实验分析体系。在1991年的第7届国际时间生物学大会GRC上首次设立了“Aschoff’s Rule”奖项,授予推动时间生物学研究的世界各国的科学家,并将Aschoff在测量节律周期时所使用的那把尺子(Aschoff’s Ruler) 作为荣誉的象征交由获奖人员短期保存。
综上所述,20世纪中叶前后是时间生物学研究领域的确立时期,诸多科学家在多个物种中的研究成果建立了相关的研究策略及技术方法,解析了生物钟调节的节律运行的行为学、生理学及遗传学基础,创立了生物钟系统的理论研究体系。Colin Pittendrigh在20世纪60年代明确了生物钟调控的周期节律具备的3个基本特征：(1)在恒定的环境条件下,内源周期节律性可自主维持近24 h节律周期性;(2)可以被光、温度等的环境信号所重置;(3)具有温度补偿的特性。鉴于Erwin Bünning(1906~1990年)、Jürgen Aschoff(1913~1998年)和Colin Pittendrigh (1919~1996年)3位****在时间生物学领域的开创性贡献,他们被尊称为“时间生物学奠基人”(图4)。
3 生物钟的分子调控机理研究(2017年诺贝尔生理或医学奖解读)
20世纪中叶,随着分子生物学和分子遗传学快速发展,科学家们开启了对生物节律分子调控机制的探索。他们早期的工作主要是利用遗传学手段在多个物种中筛选昼夜节律缺陷的突变体,并对突变基因进行遗传学定位分析,来鉴定调控昼夜节律的生物钟基因。1971年,美国遗传学家Ron Konopka和Seymour Benzer在加州理工学院以果蝇为实验材料,利用化学诱变的方法筛选得到了第一个生物钟基因突变体。他们利用了两个十分巧妙的实验设计：一是将诱变的雄性果蝇与并联X染色体(attached-X)的雌性果蝇进行交配,确保F1代雄性果蝇携带的X染色体来自父本,并可以以F1代雌性果蝇作为内部对照;二是借助野生型果蝇成虫的羽化行为主要集中在一天中的黎明时段这一特性(属于生物钟调控的果蝇的周期节律性状之一),筛选在下午或夜间时段羽化的果蝇,可极大提高突变体筛选效率[15]。他们最终筛选了约2000只果蝇,获得了3个不同的昼夜节律表型缺陷的突变品系—per0、perS、perL(分别为节律丧失、节律周期缩短和周期延长);进一步的遗传定位分析和顺反位置效应的互补测验结果显示,这3种不同的节律缺陷的表型源自果蝇同一个基因的突变,并将该基因命名为period (per)[15]。Ron Konopka和Seymour Benzer获得的per突变体具有重要的里程碑意义,让科学家认识到昼夜节律这种行为是由基因调控的,推翻了当时行为遗传学领域普遍认为的动物复杂行为不可能由单基因调控的观点。更为重要的是他们获得的突变体为后续其他科学家克隆per基因提供了重要遗传材料。1972年,美国科学家Victor G. Bruce发现了一个节律周期缩短的衣藻(Chlamydomonas reinhardi)自然变异品系,也通过化学诱变筛选得到数个生物节律突变体[16]。1973年,美国遗传学家Jerry F. Feldman(Colin Pittendrigh在美国普林斯顿大学的研究生)在加州理工学院通过对粗糙脉孢菌(Neurospora crassa)化学诱变筛选,获得了第一个真菌昼夜节律周期紊乱突变体,frequency-1 (frq1)、frq2两个周期缩短和一个周期延长(frq3)突变体[17]。图4
新窗口打开|下载原图ZIP|生成PPT图4时间生物学领域的奠基人
从左至右依次为：Erwin Bünning(1906~1990年),德国植物学家,用遗传学杂交实验证实了生物节律是机体内源可遗传性(heritability)的理论基础,并对生物钟和节律在豆科植物的光周期响应(photoperiodism)中的作用提出理论模型。Jürgen Aschoff (1913~1998年),德国生理学家,发现机体体温的24 h节律性振荡,最早展开人体的生物节律研究,还深入探讨了多个物种(小鼠、鸟类、恒河猴、人)的生物钟驯化问题,定义了“授时因子”(德文Zeitgeber,英文time giver或synchronizer)。Colin Pittendrigh(1919~1996年),英裔美国科学家,被尊称为“生物钟之父”,主要研究果蝇羽化的节律性与自然界中光信号的驯化,发展了“相位响应曲线的概念”(phase response curve),提出“非参数驯化模型”(nonparametric entrainment model),发现了节律的温度补偿现象(temperature compensation)。
Fig. 4The founders of chronobiology
1984年,美国洛克菲勒大学的Michael W. Young和Thaddeus A. Bargiello在克隆per基因时发现一段约7.1 kb的DNA序列与果蝇的生物节律相关,其转录一段4.5 kb的mRNA[18];他们利用P-element介导的基因插入技术(一种可以将基因片段插入果蝇基因组的转座子),将这段基因导入无节律的突变体果蝇per0,对其羽化行为和自发活动进行检测,发现突变体果蝇的节律性可以得到恢复,因此他们认为这段4.5 kb的mRNA对应的基因就是per基因[19]。在这项研究中,Bargiello等[19]构建的重组质粒包含果蝇的眼色基因,因此可以通过果蝇的眼色确定其是否为转基因株系。同年,来自美国布兰迪斯大学的Jeffrey C. Hall(曾经在Seymour Benzer实验室学习神经解剖学和神经化学)和Michael Rosbash研究团队利用显微切除技术获得了X染色体的3B1-2区段并对其进行了分子图谱分析。他们通过敲除果蝇per位点附近的DNA区段得到了相应的突变体果蝇,对其生理及行为节律性进行分析,将per基因定位于Df(1)K95突变体断点的右侧和Df(1)w-64d突变体断点的左侧,全长约15 kb。为进一步确定per基因的具体位置, 他们对此段DNA转录的mRNA进行了分析,发现per位点附近基因组序列的不同区段能转录多种大小、功能不同的mRNA,其中0.9 kb的mRNA在per突变体中的表达都降低了;通过在不同时间段提取果蝇细胞内的mRNA,发现这段 0.9 kb的mRNA在夜间的表达丰度要明显低于白天,所以他们当时就认为这段0.9 kb的mRNA所对应的DNA就是per基因[20]。显然,Hall团队得到了与Michael W. Young不一样的结果,而之后他们也通过P-element介导的基因插入技术进行了表型恢复实验,并对果蝇的自发活动以及雄蝇求偶歌的节律性行为进行研究,最终确定4.5 kb的mRNA对应的基因是per基因[21]。综上,果蝇per成为第一个克隆的生物钟基因,开启了对生物钟分子调控机制的研究。
哺乳动物生物钟突变体研究工作的开展略微滞后。1988年,美国科学家Martin R. Ralph和Michael Menaker在仓鼠(Mesocricetus auratus)中发现第一个哺乳动物生物节律突变体(tau),表现为明显的节律周期缩短[22]。1994年,日裔美国神经生物学家Joseph S. Takahashi通过筛选化学诱变剂处理的老鼠(Mus musculus)的F1代节律周期表型,得到一个周期延长的突变体,并将突变基因定位于第5号染色体,命名为Clock[23]。此外,1989年,粗糙脉孢菌生物钟基因frq被克隆[24];1997年,老鼠Clock基因被克隆[25],哺乳动物中Per1、Per2、Per3基因被发现[26,27],同年,拟南芥生物钟基因CIRCADIAN CLOCK-ASSOCIATED 1(CCA1)被克隆[28]。
1988年,Jeffrey C. Hall实验室开始寻找per基因产物的高效特异性抗体,希望通过抗体来定位per基因在细胞中的表达,以此标记出果蝇生物钟核心振荡器的位置。研究结果表明per基因的表达产物(PER蛋白质)主要位于果蝇眼部的感光细胞、前脑以及果蝇脑部枕叶(optic lobe,类似于哺乳动物大脑的枕叶)。虽然PER在果蝇的眼和脑部均有表达,但当时科学家认为果蝇眼中表达的PER蛋白可能是果蝇视觉系统生物钟核心振荡器的组成元件,或许有别于果蝇大脑中枢所控制的自发活动和羽化行为的核心振荡器(central oscillators)[29]。
1990年,Michael Rosbash实验室提出per基因的表达受到一种负反馈调控,PER蛋白的周期性表达依赖于per基因所编码的mRNA的周期性表达,而PER蛋白又可以通过负反馈环调控per基因所编码的mRNA的表达,因而持续而周期性地调节了自身的水平。但是当时并不知道这种调控出现在转录水平或是转录后水平,同样也不能确定这种调控是直接的还是间接的[30]。1992年,他们实验室利用免疫电镜技术对per基因的表达进行了亚细胞定位,发现PER蛋白是定位在细胞核内影响生物节律的[31]。
PER蛋白是在细胞质中被翻译的,它又是如何在细胞核中起作用的呢?1994年,Michael W. Young实验室通过P-element介导的基因插入技术,筛选出了影响生物节律的新突变体果蝇,这种突变体果蝇的羽化和活动都失去了节律性,他们把这一突变体对应的野生型基因称为timeless基因(简称tim)[32]。Vosshal等[33]发现tim影响了per基因编码的mRNA的节律性振荡,在tim突变体中,PER蛋白在核中的定位受到抑制。同年,结合已有研究成果,Amita Sehgal与Michael W. Young 提出了果蝇的生物钟调控理论模型：per和tim表达的蛋白质达到峰值时会在细胞质内结合,结合产物积累到一定数量的时候进入细胞核,并且同时抑制tim与per基因的转录;当抑制强度最大的时候,tim与per基因所编码的mRNA表达水平降到最低;如此,两种蛋白的表达量相应降低,结合产物也就减少,基因的抑制作用被解除,重新开始表达,直到第二次达到峰值[32]。1996年,Amita Sehgal实验室发现TIM蛋白可以被光降解,在进入光照条件(ZT0)之后PER-TIM蛋白复合体的数量很快地被下调[34]。上述研究成果阐述出果蝇PER蛋白的表达可调控节律的产生,但内源节律性振荡的周期长度(变化频率)的机制尚未被揭示。1998年,Michael W. Young实验室又发现了一个新的生物钟基因doubletime,其表达产物DBT蛋白(哺乳动物CKI的同源蛋白)会使PER蛋白保持磷酸化状态,增强PER蛋白的稳定性,使PER蛋白组成性的积累,进一步解释了为什么PER蛋白的振荡周期会稳定在24 h左右,完善了per/tim的调控环路[35]。
1998年,Ishiura等[36]克隆得到蓝藻生物钟核心基因kaiA、kaiB和kaiC,并提出蓝藻这一模式物种的负反馈调控模型。与真核生物中的调控机制不同,组成蓝藻生物钟的KaiA、KaiB和KaiC蛋白构成了翻译后调控的振荡器(posttranslational oscillator, PTO),在体外添加ATP的条件下,通过调节三者的比例可以重现KaiC磷酸化的节律[37]。蓝藻生物钟的研究提供了一个生物钟调控的多样性的范例。
综上所述,转录-翻译反馈环路(transcriptional translational feedback loops, TTFL)的提出确立了生物钟分子调控机制的第一个理论模型,后续研究发现该调控机制在拟南芥、粗糙脉孢菌、小鼠等多个物种均普遍存在[38,39,40,41,42,43,44,45]。鉴于Michael W. Young、Jeffrey C. Hall和Michael Rosbash在生物钟基因克隆和分子调控机制研究中的重要贡献,3位科学家在2013被授予邵逸夫奖、在2017年被授予诺贝尔生理学或医学奖。
4 时间生物学相关的关键科学问题研究
时间生物学领域关注的科学问题一直以来都是生命科学研究领域的热点方向。早在2005年,Science提出的125个人类关注的最基础的科学问题之一就包括机体生物钟的同步化如何设定[46]?生物钟与环境周期的同步化将极大提高生物体的环境适应性和生存竞争能力。在生物钟的分子调控机理方面,解析核心振荡器(core oscillators)复杂而精细的调控网络一直是生物钟研究的焦点问题。近年来除转录水平调控外,越来越多的研究表明mRNA选择性剪接、蛋白翻译过程、蛋白的修饰与降解、蛋白复合体的动态组装以及表观遗传学的调控机制在生物节律维持中也发挥着重要作用[47,48,49,50,51]。许多科学家也致力于在真核生物中寻找非TTFL的生物节律调控机制。2011年,英国科学家John S. O’Neill和Akhilesh B. Reddy发现人类成熟红细胞中存在过氧化物酶的氧化-还原节律[52];2012年,Science发表了多个研究团队的成果,证实过氧化物酶的氧化-还原节律在原核生物和真核生物细胞内普遍存在,是进化过程中保守的节律现象[53]。从原核生物蓝藻到真核单细胞生物脉孢菌,从植物到高等的哺乳动物,生物钟在漫长进化过程中得以保留和完善,大多物种的生物钟存在TTFL调控机制,但具体分子组分的同源性不高。近几年研究发现,不同物种间某些生物节律现象可能是协同进化而来,比如肠道菌群的生物节律影响宿主基因转录、表观修饰和代谢等节律现象[54];植物对于病原菌和病虫害的防御能力存在时间依赖性,两者的生物节律在进化过程中达到某种平衡才得以共同生存[55,56];生物钟调控使得向日葵在清晨之前将花盘朝向太阳可能是为了尽快使花盘温暖,从而吸引更多的昆虫传粉[57];帝王蝶触角中生物钟调控为其长时程的定向迁徙提供时间补偿[58,59]。因此,生物钟在物种进化、季节响应与环境适应性等相关问题的研究是非常有价值的切入点。
植物生物钟及生物节律调控着包括农作物的生长发育、新陈代谢和多种逆境胁迫响应等过程。研究表明,生物钟在调控多种单、双子叶作物的农艺性状方面具有着重要作用[60,61,62]。拟南芥生物钟核心组分CCA1可能参与植物的杂种优势[63];白菜(Brassica rapa)的GIGANTEA (GI)调控植物下胚轴伸长、光周期对开花时间的调控、低温胁迫及盐胁迫响应[64];生物钟调控甘蓝等多种蔬菜和水果的后熟、储存和运输过程中保鲜和营养成分代谢[65];拟南芥生物钟夜间复合体的重要组分ELF3在大豆中同源基因J的突变对于大豆适应低纬度地区环境至关重要[66]。未来有望通过调控农作物的内源生物节律,获得适应不同季节和生长环境的作物,提高全球农作物的产量和品质。
生物钟与人类的健康息息相关,例如昼夜节律性睡眠障碍是常见的睡眠疾病,主要是由于生物钟紊乱或环境改变导致睡眠节律与生物钟不同步导致,会严重影响患者的身心健康、精神状态和生活质量,通过强光照射或服用褪黑激素等能够重置生物节律的手段调节生物钟与睡眠节律以及环境节律同步化,能够有效缓解或治疗病症[67]。近年来的研究表明,生物钟与肥胖、老年痴呆、衰老、癌症、生殖和新陈代谢缺陷等多种疾病的发生相关[68,69,70,71,72],通过对生物钟基础理论研究成果的应用或生物钟相关靶向药物的开发可以为生物节律相关疾病提供更好的诊断和治疗方案。近年来生物钟核心期刊发表的关键科学问题还包括：生物钟与组织稳态调控、生物钟与干细胞调控、生物钟与肿瘤治疗、光污染对健康、生物钟与免疫系统疾病、动植物的日节律与季节节律等[68,73~79]。
综上所述,时间生物学领域的科学问题十分广泛,对于生物钟调控机制研究的关注点已经逐渐从机体水平深入到组织和细胞水平,其中生物钟与组织稳态(tissue homeostasis)相关研究成为生物钟基础理论研究的热点之一。位于哺乳动物下丘脑的视交叉上核(suprachiasmatic nucleus, SCN)作为控制中心调控整个机体的生物节律,通过神经中枢和激素分泌等较直接的途径或者调控体温、进食等较间接方式实现SCN与外周生物钟系统的同步化[80]。另一方面,组成SCN的约20 000个神经元均有自主的生物钟,它们的功能存在差异,比如产生精氨酸加压素(arginine vasopressin, AVP)的神经元细胞可能对于调控整个SCN神经元网络的信息交流十分关键[81]。对组织器官和细胞水平生物钟及同步化的探索,将更精准、系统地阐释机体生物钟的时空调控机理。
参考文献 原文顺序
文献年度倒序
文中引用次数倒序
被引期刊影响因子
[本文引用: 1]
[本文引用: 1]
URL [本文引用: 1]
This is an EXACT reproduction of a book published before 1923. This IS NOT an OCR'd book with strange characters, introduced typographical errors, and jumbled words. This book may have occasional imperfections such as missing or blurred pages, poor pictures, errant marks, etc. that were either part of the original artifact, or were introduced by the scanning process. We believe this work is culturally important, and despite the imperfections, have elected to bring it back into print as part of our continuing commitment to the preservation of printed works worldwide. We appreciate your understanding of the imperfections in the preservation process, and hope you enjoy this valuable book.
URL [本文引用: 1]
Abstract Emphasizes the spontaneous activity of the organism (that is occasioned by internal stimuli) in contrast to the typical sensory discrimination or motor learning problem, in which the capacity of the organism to respond to definite external stimuli is measured. A sound-proof dark room in which the temperature was kept constant and in which odors were eliminated by means of a ventilation system was used. The measurement of the activity of the rat was made in terms of the number of times a revolving drum was rotated during a given interval, or by means of a kymographic record of the movement of a 'stationary activity case' in which the animal was placed. The results indicated that the spontaneous activity of the rat was periodic and that the periods of activity became shorter and less frequent with the increasing age of the animal. When animals were starved for eight days, a definite increase in activity was shown for the first two or three days, followed by steady decrease to the point of almost total inactivity on the eighth day. When animals were deprived of water, activity decreased till complete inactivity occurred on the fifth day. Activity also varied with changes in temperature from a normal of 23掳 C., the maximum diurnal activity beginning almost immediately after feeding when the temperature was lowered to 10掳 to 15掳 C., whereas the period of quiescence following feeding was greatly lengthened by raising the temperature to 30掳 C. The rats were found to be more active in the dark than in the light and became progressively nocturnal with increasing age. The rhythms of activity once established, tended to persist even after the removal of the rhythmic stimulus. From Psych Bulletin 21:12:01275. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
[本文引用: 1]
URL [本文引用: 2]
In this translation (with additions) of the 2nd German edition, the author has attempted to emphasize the physiological kinship of phenomena in plants and animals influenced by circadian rhythms, and to analyse the mechanism of the biological clock as thoroughly as is at present possible.-J.G.G.
URL [本文引用: 1]
Es wird eine Methode beschrieben, die es gestattet, die phototaktische Sensibilit01t von Algen mit Hilfe eines Photoelementes objektiv zu messen. Bei automatischer Registrierung der Gr0208e der Phototaxis über einen l01ngeren Zeitraum konnte ein Tagesrhythmus im phototaktischen Verhalten von Euglena gracilis nachgewiesen werden. Die Versuchsergebnisse deuten auf einen endogenen Charakter dieses Rhythmus bei Euglena gracilis hin.
URL [本文引用: 1]
[本文引用: 1]
URL [本文引用: 1]
Fii'ty grams of powdered lyophilized beef pineal glands6 was extracted with petroleum ether for two hours in a soxhlet extractor. The defatted powder was mixed with 900 ml. water in a JT-aring Blendor. After centrifugation at 16,000 X g for 30 minutes the supernatant was
URLPMID:6823571 [本文引用: 1]
The pineal gland hormone melatonin may play a role in synchronization of rat circadian rhythms. Free-running activity rhythms of the rat were entrained by a daily melatonin injection, with entrainment occurring when the onset of activity coincided with the time of daily injections. When injections were stopped, activity rhythms became free-running again. Thus in pharmacological experiments, the time of day of melatonin administration is crucial.
URL [本文引用: 1]
Not Available
[本文引用: 1]
URLPMID:6542316 [本文引用: 1]
Abstract A neural model of the suprachiasmatic nuclei suggests how behavioral activity, rest, and circadian period depend on light intensity in diurnal and nocturnal mammals. These properties are traced to the action of light input (external zeitgeber) and an activity-mediated fatigue signal (internal zeitgeber) on the circadian pacemaker. Light enhances activity of the diurnal model and suppresses activity of the nocturnal model. Fatigue suppresses activity in both diurnal and nocturnal models. The asymmetrical action of light and fatigue in diurnal vs. nocturnal models explains the more consistent adherence of nocturnal mammals to Aschoff's rule, the consistent adherence of both diurnal and nocturnal mammals to the circadian rule, and the tendency of nocturnal mammals to lose circadian rhythmicity at lower light levels than diurnal mammals. The fatigue signal is related to the sleep process S of Borb茅ly (Hum. Neurobiol. 1: 195-204, 1982.) and contributes to the stability of circadian period. Two predictions follow: diurnal mammals obey Aschoff's rule less consistently during a self-selected light-dark cycle than in constant light, and if light level is increased enough during sleep in diurnal mammals to compensate for eye closure, then Aschoff's rule will hold more consistently. The results are compared with those of Enright's model.
[本文引用: 2]
URL [本文引用: 1]
ABSTRACT A genetic analysis of the hiolcgical clock in Chlamydomonas reinhardi has been initiated. Of six wild-type strains tested (3 mtf and 3 me), five had pe- riods close to 2+ hr whereas one had a 21-hr period. Mutants with altered clock period have been isolated. The periods of 3 of these variant strains are temper- ature compensated. Genetic crosses involving a long-period mutant suggest that a single gene confers the long-period character, and in general clock-period length seems to be a useful pheiictypic measure of alterations in the clock due to genetic differences. One phase mutant was found but its behavior was varia- ble and the phase of the rhythm, relative to a light-dark transition which ini- tiates the rhythm, does not seem to be reliable as a parameter of clock differ- ences. No markers have yet been mapped. BIOLOGICAL clocks are thought to have period lengths determined by selec- tion to serve an adaptive function. There are differences in the periods of individuals within a species and between species but these differences are small and all of the periods are circadian. In the first genetic experiments on clocks BUNNING (1935) made hybrids of bean plants which had different clock periods and the periods of the hybrids were found to be intermediate in value between those of the parental species. He suggested that the controlling factors were poly- genic. The periods of activity rhythms of individual rodents and other animals are different but little has been done to investigate the extent to which these dif- ferences are of genetic origin. Recent studies with insects and microorganisms indicate that mutants with altered clock periods can be obtained. Clock-period mutants have been found in Neurospora (FELDMAN 1971), and Drosophila ( KONOPK and BENZER 1971 ) . A second aspect of genetic experiments with circadian rhythms is the coupling of the "driving o~cillation~~ with the physiological or behavioral characteristic which it controls. PITTENDRIGH (1967) gave a detailed explicit description of this. He showed that the clock-controlled emergence time of Drosophila can be changed by selection (up to 50 generations) so that the "early" selected strain emerges 4 hr earlier (on a 24-hr time scale) than the "late" selected strain. How- ever, the free-running periods of the two selected strains are almost identical; it is the coupling between the controlling oscillation and the emergence rhythm which has been modified by selection. BARNETT (1966) working with a rhythm
[本文引用: 1]
[本文引用: 1]
URLPMID:6440029 [本文引用: 2]
The per locus of Drosophila melanogaster has a fundamental role in the construction or maintenance of a biological clock. Three classes of per mutations have been identified: per l mutants have circadian behavioural rhythms with a 29-h rather than a 24-h period, per s mutants have short-period rhythms of 19 h and per 0 mutants have no detectable circadian rhythms 1鈥4 . Each of these mutations has a corresponding influence on the 55-s periodicity of male courtship song 5 . Long-and short-period circadian rhythm phenotypes can also be obtained by altering the dosage of the wild-type gene 4 : for example, females carrying only one dose of this X-linked gene have circadian rhythms with periodicities about 1 h longer than those carrying two doses. In a previous report 6 , cloned DNA was used to localize several chromosomal rearrangement breakpoints that alter per locus function. The rearrangements all affected a 7-kilobase (kb) interval that encodes a 4.5-kb poly(A) + RNA. We report here that when a 7.1-kb fragment from a per + fly, including the sequences encoding the 4.5-kb transcript, is introduced into the genome of a per 0 (arrhythmic) fly by P element-mediated transformation, circadian rhythmicity of behaviour such as eclosion and locomotor activity is restored. The transforming DNA complements per locus deletions and is transcribed, forming a single 4.5-kb poly(A) + RNA comparableto that produced by wild-type flies.
URLPMID:6435882 [本文引用: 1]
Abstract We have isolated and analyzed DNA sequences encompassing the period (per) locus of Drosophila melanogaster. The location of this clock gene was delimited by the molecular mapping of chromosome aberrations at or very near the per locus. At least five RNAs are transcribed from this region. One of these transcripts, a 0.9 kb species, is strongly implicated in per's control of biological rhythms. Two independently isolated arrhythmic mutations at the per locus dramatically reduce the level of this transcript. Furthermore, the level of the 0.9 kb transcript is strongly modulated during a light/dark cycle. We discuss evidence, from previously reported genetic and phenotypic analysis of per's function, suggesting that this region may be complex and that several gene products from the per region, including this 0.9 kb transcript, may be involved in the different aspects of normal rhythmicity influenced by this clock gene.
URLPMID:6094014 [本文引用: 1]
Mutations at the period (per) locus of Drosophila melanogaster disrupt several biological rhythms. Molecular cloning of DNA sequences encompassing the per + locus has allowed germ-line transformation experiments to be carried out. Certain subsegments of the per region, transduced into the genome of arrhythmic per o flies, restore rhythmicity in circadian locomotor behavior and the male's courtship song.
URL [本文引用: 1]
URL [本文引用: 1]
URLPMID:2563175 [本文引用: 1]
To investigate the regulation of messenger RNA abundance by circadian clocks, genomic and complementary DNA libraries were screened with complementary DNA probes enriched, by means of sequential rounds of subtractive hybridization, for sequences complementary to transcripts specific to either early morning or early evening cultures of Neurospora. Only two morning-specific genes were identified through this protocol. RNA blot analysis verified that the abundance of the transcripts arising from these genes oscillates with a period of 21.5 hours in a clock wild-type strain and 29 hours in the long-period clock mutant strain frq7. Genetic mapping through the use of restriction fragment length polymorphisms shows the two genes, ccg-1 and ccg-2, to be unlinked. These data provide a view of the extent of clock control of gene expression.
URLPMID:9160755 [本文引用: 1]
We used positional cloning to identify the circadian Clock gene in mice. Clock is a large transcription unit with 24 exons spanning approximately 100,000 bp of DNA from which transcript classes of 7.5 and approximately 10 kb arise. Clock encodes a novel member of the bHLH-PAS family of transcription factors. In the Clock mutant allele, an A-->T nucleotide transversion in a splice donor site causes exon skipping and deletion of 51 amino acids in the CLOCK protein. Clock is a unique gene with known circadian function and with features predicting DNA binding, protein dimerization, and activation domains. CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism.
URLPMID:9427249 [本文引用: 1]
We have characterized a mammalian homolog of the Drosophila period gene and designated it Per2. The PER2 protein shows >40% amino acid identity to the protein of another mammalian per homolog (designated Per1) that was recently cloned and characterized. Both PER1 and PER2 proteins share several regions of homology with the Drosophila PER protein, including the protein dimerization PAS domain. Phylogenetic analysis supports the existence of a family of mammalian per genes. In the mouse, Per1 and Per2 RNA levels exhibit circadian rhythms in the SCN and eyes, sites of circadian clocks. Both Per1 and Per2 RNAs in the SCN are increased by light exposure during subjective night but not during subjective day. The results advance our knowledge of candidate clock elements in mammals.
[本文引用: 1]
URL [本文引用: 1]
URLPMID:3152288 [本文引用: 1]
Abstract Polyclonal antibodies were prepared against the period gene product, which influences biological rhythms in D. melanogaster, by using small synthetic peptides from the per sequence as immunogens. The peptide that elicited the best antibody reagent was a small domain near the site of the pers (short period) mutation. Specific immunohistochemical staining was detected in a variety of tissue types: the embryonic CNS; a few cell bodies in the central brain of pupae; these and other cells in the central brain of adults, as well as imaginal cells in the eyes, optic lobes, and the gut. The intensity of per-specific staining in the visual system was found to oscillate, defining a free-running circadian rhythm with a peak in the middle of the night.
URLPMID:2105471 [本文引用: 1]
Mutations in the period ( per ) gene of Drosophila melanogaster affect both circadian and ultradian rhythms. Levels of per gene product undergo circadian oscillation and it is now shown that there is an underlying oscillation in the level of per RNA. The observations indicate that the cycling of per -encoded protein could result from per RNA cycling and that there is a feedback loop through which the activity of per -encoded protein causes cycling of its own RNA.
URLPMID:1613555 [本文引用: 1]
The period gene of Drosophila melanogaster (per) is important for the generation and maintenance of biological rhythms. Previous light microscopic observations indicated that per is expressed in a variety of tissues and cell types and suggested that the per protein (PER) may be present in different subcellular compartments. To understand how PER influences circadian rhythms, it is important to define its subcellular location, especially in adult flies where inducible promoter experiments suggested that it is most relevant to circadian locomotor activity rhythms. To this end, we report the results of an immunoelectron microscopic analysis of wild-type flies and per-beta-galactosidase (beta-gal) fusion gene transgenics using a polyclonal anti-PER antibody or an anti-beta-gal antibody, respectively. Most of the PER antigen and the fusion gene product were located within nuclei, suggesting that PER acts in that subcellular compartment to affect circadian rhythms. The results are discussed in terms of per's possible biochemical functions.
URL [本文引用: 2]
URLPMID:8128247 [本文引用: 1]
In wild-type Drosophila, the period protein (PER) is found in nuclei of the eyes and brain, and PER immunoreactivity oscillates with a circadian rhythm. The studies described here indicate that the nuclear localization of PER is blocked by timeless (tim), a second chromosome mutation that, like per null mutations, abolishes circadian rhythms. PER fusion proteins without a conserved domain (PAS) and some flanking sequences are nuclear in tim mutants. This suggests that a segment of PER inhibits nuclear localization in tim mutants. The tim gene may have a role in establishing rhythms of PER abundance and nuclear localization in wild-type flies.
URLPMID:8625406 [本文引用: 1]
Abstract Circadian behavioral rhythms in Drosophila depend on the appropriate regulation of at least two genes, period (per) and timeless (tim). Previous studies demonstrated that levels of PER and TIM RNA cycle with the same phase and that the PER and TIM proteins interact directly. Here we show the cyclic expression of TIM protein in adult heads and report that it lags behind peak levels of TIM RNA by several hours. We alsoshow that nuclear expression of TIM depends upon the expression of PER protein. Finally, we report that the expression of TIM, but not PER, is rapidly reduced by light, suggesting that TIM mediates light-induced resetting of the circadian clock. Since both PER and TIM RNA are unaffected by light treatment, the effects of light on TIM appear to be posttranscriptional.
[本文引用: 1]
URLPMID:9727980 [本文引用: 1]
Cyanobacteria are the simplest organisms known to have a circadian clock. A circadian clock gene cluster kaiABC was cloned from the cyanobacterium Synechococcus. Nineteen clock mutations were mapped to the three kai genes. Promoter activities upstream of the kaiA and kaiB genes showed circadian rhythms of expression, and both kaiA and kaiBC messenger RNAs displayed circadian cycling. Inactivation of any single kai gene abolished these rhythms and reduced kaiBC-promoter activity. Continuous kaiC overexpression repressed the kaiBC promoter, whereas kaiA overexpression enhanced it. Temporal kaiC overexpression reset the phase of the rhythms. Thus, a negative feedback control of kaiC expression by KaiC generates a circadian oscillation in cyanobacteria, and KaiA sustains the oscillation by enhancing kaiC expression.
URL [本文引用: 1]
URLPMID:8128244 [本文引用: 1]
The frequency (frq) locus of Neurospora crassa was originally identified in searches for loci encoding components of the circadian clock. The frq gene is now shown to encode a central component in a molecular feedback loop in which the product of frq negatively regulated its own transcript, which resulted in a daily oscillation in the amount of frq transcript. Rhythmic messenger RNA expression was essential for overt rhythmicity in the organism and no amount of constitutive expression rescued normal rhythmicity in frq loss-of-function mutants. Step reductions in the amount of FRQ-encoding transcript set the clock to a specific and predicted phase. These results establish frq as encoding a central component in a circadian oscillator.
[本文引用: 1]
URLPMID:3946763 [本文引用: 1]
Circadian clocks coordinate physiology and behavior with the 24h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcriptional and post-transcriptional mechanisms to impart temporal control onto mammalian physiology. Understanding the way in which biological rhythms are generated throughout the body may provide avenues for temporally directed therapeutics to improve health and prevent disease.
URLMagsci [本文引用: 1]
<p>生物钟几乎参与调控了植物体所有的新陈代谢、生长发育过程，使植物体与外界环境条件达到时间和空间的<br />同步，极大地增强了植物环境适应性和竞争能力。笔者首先从植物生物钟的研究历史入手，回顾了中国古代农业生<br />产中对节律性的认识和应用；然后介绍了现代植物生物钟研究的起源、基本概念和理论知识；最后重点论述了本领<br />域的最新研究进展，揭示了植物生物钟作为复杂的信号转导网络的“整体水平”调控特性和“牵一发而动全身”的<br />独特性。</p>
URLMagsci [本文引用: 1]
<p>生物钟几乎参与调控了植物体所有的新陈代谢、生长发育过程，使植物体与外界环境条件达到时间和空间的<br />同步，极大地增强了植物环境适应性和竞争能力。笔者首先从植物生物钟的研究历史入手，回顾了中国古代农业生<br />产中对节律性的认识和应用；然后介绍了现代植物生物钟研究的起源、基本概念和理论知识；最后重点论述了本领<br />域的最新研究进展，揭示了植物生物钟作为复杂的信号转导网络的“整体水平”调控特性和“牵一发而动全身”的<br />独特性。</p>
URLPMID:22421040 [本文引用: 1]
For 20 years, researchers have thought that circadian clocks are defined by feedback loops of transcription and translation. The rediscovery of posttranslational circadian oscillators in diverse organisms forces us to rethink this paradigm. Meanwhile, the original “basic” feedback loops of canonical circadian clocks have swelled to include dozens of additional proteins acting in interlocked loops. We review several self-sustained clock mechanisms and propose that minimum requirements for diurnal timekeeping might be simpler than those of actual free-running circadian oscillators. Thus, complex mechanisms of circadian timekeeping might have evolved from random connections between unrelated feedback loops with independent but limited time-telling capability.
URL [本文引用: 1]
地球以24 h为自转周期,为此,生活在地球上的不同生物也通过自身约24 h的内在节律的形成来适应昼夜环境的变化,这一系统即为生物钟。在哺乳类动物中,生物钟主要通过涵盖转录与翻译水平的核心连锁环驱动特异性的转录因子来维持整个基因组转录的昼夜节律性,从而使得不同组织与器官的生理功能能够适应环境剧烈的昼夜变化。现将在综述哺乳类动物昼夜节律形成机制及其生理功能研究进展的基础上,对今后的研究方向作出展望。
URL [本文引用: 1]
地球以24 h为自转周期,为此,生活在地球上的不同生物也通过自身约24 h的内在节律的形成来适应昼夜环境的变化,这一系统即为生物钟。在哺乳类动物中,生物钟主要通过涵盖转录与翻译水平的核心连锁环驱动特异性的转录因子来维持整个基因组转录的昼夜节律性,从而使得不同组织与器官的生理功能能够适应环境剧烈的昼夜变化。现将在综述哺乳类动物昼夜节律形成机制及其生理功能研究进展的基础上,对今后的研究方向作出展望。
URL [本文引用: 1]
URL [本文引用: 1]
URLMagsci [本文引用: 1]
斑马鱼是生物钟研究领域中一种新兴的脊椎动物模型。文章总结了斑马鱼生物钟研究的一些进展, 以及利用斑马鱼研究生物钟的特点及优势。由于光照和温度作为重要的外部信号在斑马鱼生物钟调节中发挥重要作用, 文章主要就近期光和温度对斑马鱼钟基因及调节通路的研究进行了概述, 最后对斑马鱼生物钟研究的未来提出了展望。
URLMagsci [本文引用: 1]
斑马鱼是生物钟研究领域中一种新兴的脊椎动物模型。文章总结了斑马鱼生物钟研究的一些进展, 以及利用斑马鱼研究生物钟的特点及优势。由于光照和温度作为重要的外部信号在斑马鱼生物钟调节中发挥重要作用, 文章主要就近期光和温度对斑马鱼钟基因及调节通路的研究进行了概述, 最后对斑马鱼生物钟研究的未来提出了展望。
[本文引用: 1]
URL [本文引用: 1]
URLPMID:24449901 [本文引用: 1]
Posttranslational regulation of clock proteins is an essential part of mammalian circadian rhythms, conferring sensitivity to metabolic state and offering promising targets for pharmacological control. Two such regulators, casein kinase 1 (CKI) and F-box and leucine-rich repeat protein 3 (FBXL3), modulate the stability of closely linked core clock proteins period (PER) and cryptochrome (CRY), respectively. Inhibition of either CKI or FBXL3 leads to longer periods, and their effects are independent despite targeting proteins with similar roles in clock function. A mechanistic understanding of this independence, however, has remained elusive. Our analysis of cellular circadian clock gene reporters further differentiated between the actions of CKI and FBXL3 by revealing opposite amplitude responses from each manipulation. To understand the functional relationship between the CKI-PER and FBXL3-CRY pathways, we generated robust mechanistic predictions by applying a bootstrap uncertainty analysis to multiple mathematical circadian models. Our results indicate that CKI primarily regulates the accumulating phase of the PER-CRY repressive complex by controlling the nuclear import rate, whereas FBXL3 separately regulates the duration of transcriptional repression in the nucleus. Dynamic simulations confirmed that this spatiotemporal separation is able to reproduce the independence of the two regulators in period regulation, as well as their opposite amplitude effect. As a result, this study provides further insight into the molecular clock machinery responsible for maintaining robust circadian rhythms.
URLPMID:19740663 [本文引用: 1]
The pace has quickened in circadian biology research. In particular, an abundance of results focused on post-translational modifications (PTMs) is sharpening our view of circadian molecular clockworks. PTMs affect nearly all aspects of clock biology; in some cases they are essential for clock function and in others, they provide layers of regulatory fine-tuning. Our goal is to review recent advances in clock PTMs, help make sense of emerging themes, and spotlight intriguing (and perhaps controversial) new findings. We focus on PTMs affecting the core functions of eukaryotic clocks, in particular the functionally related oscillators in Neurospora crassa, Drosophila melanogaster, and mammalian cells.
URLPMID:24481076 [本文引用: 1]
The circadian clock is a cellular time-keeper mechanism that regulates biological rhythms with a period of ~24 h. The circadian rhythms in metabolism, physiology, and development are synchronized by environmental cues such as light and temperature. In plants, proper matching of the internal circadian time with the external environment confers fitness advantages on plant survival and propagation. Accordingly, plants have evolved elaborated regulatory mechanisms that precisely control the circadian oscillations. Transcriptional feedback regulation of several clock components has been well characterized over the past years. However, the importance of additional regulatory mechanisms such as chromatin remodeling, protein complexes, protein phosphorylation, and stability is only starting to emerge. The multiple layers of circadian regulation enable plants to properly synchronize with the environmental cycles and to fine-tune the circadian oscillations. This review focuses on the diverse posttranslational events that regulate circadian clock function. We discuss the mechanistic insights explaining how plants articulate a high degree of complexity in their regulatory networks to maintain circadian homeostasis and to generate highly precise waveforms of circadian expression and activity.
URL [本文引用: 1]
URL [本文引用: 1]
URLPMID:21270888 [本文引用: 1]
Circadian (鈭24 hour) clocks are fundamentally important for coordinated physiology in organisms as diverse as cyanobacteria and humans. All current models of the molecular circadian clockwork in eukaryotic cells are based on transcription-translation feedback loops. Non-transcriptional mechanisms in the clockwork have been difficult to study in mammalian systems. We circumvented these problems by developing novel assays using human red blood cells, which have no nucleus (or DNA) and therefore cannot perform transcription. Our results show that transcription is not required for circadian oscillations in humans, and that non-transcriptional events seem to be sufficient to sustain cellular circadian rhythms. Using red blood cells, we found that peroxiredoxins, highly conserved antioxidant proteins, undergo 鈭24-hour redox cycles, which persist for many days under constant conditions (that is, in the absence of external cues). Moreover, these rhythms are entrainable (that is, tunable by environmental stimuli) and temperature-compensated, both key features of circadian rhythms. We anticipate that our findings will facilitate more sophisticated cellular clock models, highlighting the interdependency of transcriptional and non-transcriptional oscillations in potentially all eukaryotic cells.
URLPMID:3398137 [本文引用: 1]
Cellular life emerged 653.765billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles owing to the Earth's rotation. The advantage conferred on organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation-reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterizing their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription-translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular timekeeping with redox homeostatic mechanisms after the Great Oxidation Event 652.565billion years ago.
URLPMID:27912059 [本文引用: 1]
The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.
URLPMID:21293378 [本文引用: 1]
Abstract The principal immune mechanism against biotrophic pathogens in plants is the resistance (R)-gene-mediated defence. It was proposed to share components with the broad-spectrum basal defence machinery. However, the underlying molecular mechanism is largely unknown. Here we report the identification of novel genes involved in R-gene-mediated resistance against downy mildew in Arabidopsis and their regulatory control by the circadian regulator, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1). Numerical clustering based on phenotypes of these gene mutants revealed that programmed cell death (PCD) is the major contributor to resistance. Mutants compromised in the R-gene-mediated PCD were also defective in basal resistance, establishing an interconnection between these two distinct defence mechanisms. Surprisingly, we found that these new defence genes are under circadian control by CCA1, allowing plants to 'anticipate' infection at dawn when the pathogen normally disperses the spores and time immune responses according to the perception of different pathogenic signals upon infection. Temporal control of the defence genes by CCA1 differentiates their involvement in basal and R-gene-mediated defence. Our study has revealed a key functional link between the circadian clock and plant immunity.
URL [本文引用: 1]
URLPMID:27493185 [本文引用: 1]
Abstract Young sunflower plants track the Sun from east to west during the day and then reorient during the night to face east in anticipation of dawn. In contrast, mature plants cease movement with their flower heads facing east. We show that circadian regulation of directional growth pathways accounts for both phenomena and leads to increased vegetative biomass and enhanced pollinator visits to flowers. Solar tracking movements are driven by antiphasic patterns of elongation on the east and west sides of the stem. Genes implicated in control of phototropic growth, but not clock genes, are differentially expressed on the opposite sides of solar tracking stems. Thus, interactions between environmental response pathways and the internal circadian oscillator coordinate physiological processes with predictable changes in the environment to influence growth and reproduction. Copyright 脗漏 2016, American Association for the Advancement of Science.
URLPMID:26473314 [本文引用: 1]
Studies of the migration of the eastern North butterfly () have revealed mechanisms behind its navigation. The main orientation mechanism uses a time-compensated sun compass during both the migration south and the remigration north. Daylight cues, such as the sun itself and polarized light, are processed through both eyes and integrated through intricate circuitry in the brain's central complex, the presumed site of the sun compass. Monarch circadian clocks have a distinct molecular mechanism, and those that reside in the antennae provide time compensation. Recent evidence shows that migrants can also use a lightdependent inclination magnetic compass for orientation in the absence of directional daylight cues. The monarch genome has been sequenced, and genetic strategies using -based technologies have been developed to edit specific genes. The has emerged as a model system to study the neural, molecular, and genetic basis of long-distance animal migration. Expected final online publication date for the Annual Review of Entomology Volume 61 is January 07, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
URL [本文引用: 1]
URLPMID:28153924 [本文引用: 1]
react-text: 159 In cotton, gossypol and related sesquiterpene aldehydes are present in the glands of aerial tissues and in epidermal cells of roots. A cytochrome P450 was found to be expressed in aerial tissues of glanded cotton cultivars, but not or at an extremely low level in the aerial tissues of a glandless cultivar. Its cDNA was then isolated from Gossypium arboreum L. After expression in Saccharomyces... /react-text react-text: 160 /react-text [Show full abstract]
URLPMID:25772379 [本文引用: 1]
生理节奏的钟是使植物能同步的内长的定时器有每日、季节的环境条件的生物过程以便在白天和年的最有益的时间期间分配资源。生理节奏的钟调整很多项中央植物活动，包括生长，开发，和复制，首先通过控制 transcriptional 活动和蛋白质功能的一个实质的比例。这评论检验生理节奏的钟基因的等位基因在庄稼植物的驯服和改进起了的作用。这里的焦点在到在 Arabidopsis thaliana 的钟功能的三组生理节奏的钟基因必需品上：伪反应管理者， GIGANTEA，和晚上建筑群基因早 FLOWERING 3，早 FLOWERING 4，并且勒克司 ARRHYTHMO。从每个组的相应基因位于量的特点 loci 下面在关键农业特点，特别 flowering 时间而且收益上有有益的影响，生物资源，和二年的生长习惯。包括对不能生活、关於生命的压力的回答，进另外的基本植物过程的生理节奏的钟规定的新兴的卓见被讨论为进一步的庄稼改进加亮有希望的大街。
URL [本文引用: 1]
生物钟参与调控植物体几乎全部的生长发育和新陈代谢过程,赋予植物体"预知"外界环境条件变化的能力,使得其生理生化反应与外界环境达到时空同步,从而获取更多的资源,减少能量消耗,增强植物体环境适应性和竞争能力。现概括介绍了植物生物钟领域的最新研究进展,包括由核心调控组分构成的多重转录-翻译反馈环路,特别强调了生物钟输出途径的研究成果,以期促进生物钟基础理论研究应用于农业生产的可行性探索。
URL [本文引用: 1]
生物钟参与调控植物体几乎全部的生长发育和新陈代谢过程,赋予植物体"预知"外界环境条件变化的能力,使得其生理生化反应与外界环境达到时空同步,从而获取更多的资源,减少能量消耗,增强植物体环境适应性和竞争能力。现概括介绍了植物生物钟领域的最新研究进展,包括由核心调控组分构成的多重转录-翻译反馈环路,特别强调了生物钟输出途径的研究成果,以期促进生物钟基础理论研究应用于农业生产的可行性探索。
URLPMID:19029881 [本文引用: 1]
Segregating hybrids and stable allopolyploids display morphological vigour, and Arabidopsis allotetraploids are larger than the parents Arabidopsis thaliana and Arabidopsis arenosa-the mechanisms for this are unknown. Circadian clocks mediate metabolic pathways and increase fitness in animals and plants. Here we report that epigenetic modifications of the circadian clock genes CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) and their reciprocal regulators TIMING OF CAB EXPRESSION 1 (TOC1) and GIGANTEA (GI) mediate expression changes in downstream genes and pathways. During the day, epigenetic repression of CCA1 and LHY induced the expression of TOC1, GI and downstream genes containing evening elements in chlorophyll and starch metabolic pathways in allotetraploids and F(1) hybrids, which produced more chlorophyll and starch than the parents in the same environment. Mutations in cca1 and cca1 lhy and the daily repression of cca1 by RNA interference (RNAi) in TOC1::cca1(RNAi) transgenic plants increased the expression of downstream genes and increased chlorophyll and starch content, whereas constitutively expressing CCA1 or ectopically expressing TOC1::CCA1 had the opposite effect. The causal effects of CCA1 on output traits suggest that hybrids and allopolyploids gain advantages from the control of circadian-mediated physiological and metabolic pathways, leading to growth vigour and increased biomass.
[本文引用: 1]
URLPMID:23791724 [本文引用: 1]
The modular design of plants enables individual plant organs to manifest autonomous functions [ 1 ] and continue aspects of metabolism, such as respiration, even after separation from the parent plant [ 2 ]. Therefore, we hypothesized that harvested vegetables and fruits may retain capacity to perceive and respond to external stimuli. For example, thefitness advantage of plant circadian clock function is recognized [ 3 聽and聽 4 ]; however, whether the clock continues to influence postharvest physiology is unclear. Here we demonstrate that the circadian clock of postharvest cabbage ( Brassica oleracea ) is entrainable by light-dark cycles and results in enhanced herbivore resistance. In addition, entrainment of Arabidopsis plants and postharvest cabbage causes cyclical accumulation of metabolites that function in plant defense; in edible crops, these metabolites also have potent anticancer properties [ 5 ]. Finally, weshow that the phenomena of postharvest entrainment and enhanced herbivore resistance are widespread among diverse crops. Therefore, sustained clock entrainment of postharvest crops may be a simple mechanism to promote pest resistance and nutritional value of plant-derived food.
URLPMID:28319089 [本文引用: 1]
Fanjiang Kong, Zhixi Tian, Xingliang Hou, Baohui Liu and colleagues report the cloning and functional characterization of J, the locus underlying the long-juvenile (LJ) trait that has enabled tropical cultivation of soybean. They show that J, an ortholog of Arabidopsis ELF3, downregulates the expression of E1, thereby promoting flowering under short-day conditions.
URL [本文引用: 1]
URL [本文引用: 1]
URLPMID:28802039 [本文引用: 2]
SummaryThe process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.
URLPMID:4351409 [本文引用: 1]
Abstract Disturbances in the sleep-wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep-wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep-wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep-wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.
URLPMID:24099911 [本文引用: 1]
Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24h day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix/PAS domain containing transcription factors; Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular examples exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I inhibitors and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock.
URLPMID:27218855 [本文引用: 1]
Abstract Epidemiological studies provided the first evidence suggesting a connection between the circadian clock and human health. Mutant mice convincingly demonstrate the principle that dysregulation of the circadian system leads to a multitude of pathologies. Chrono-medicine is one of the most important upcoming themes in the field of circadian biology. Although treatments counteracting circadian dysregulation are already being applied (e.g., prescribing strong and regular zeitgebers), we need to comprehend entrainment throughout the body's entire circadian network before understanding the mechanisms that tie circadian dysregulation to pathology. Here, we attempt to provide a systematic approach to understanding the connection between the circadian clock and health. This taxonomy of (mis)alignments on one hand exposes how little we know about entrainment within any organism and which 'eigen-zeitgeber' signals are used for entrainment by the different cells and tissues. On the other hand, it provides focus for experimental approaches and tools that will logically map out how circadian systems contribute to disease as well as how we can treat and prevent them. Copyright 脗漏 2016 Elsevier Ltd. All rights reserved.
URLMagsci [本文引用: 1]
<P>由生物体内源性生物钟所产生的昼夜节律是近年来生命科学的研究热点之一。哺乳动物中的昼夜节律系统由位于下丘脑SCN核内的主钟和位于多数外周细胞中的子钟组成。生物钟基因及其编码的蛋白质组成反馈回路,维持振荡系统持续进行并与环境周期保持同步。光照和食物是生物钟重要的授时因子, 光照刺激能引起肾上腺中基因表达变化以及糖皮质激素的分泌, 而肾上腺糖皮质激素能减缓由食物因子引起的外周生物钟时相的移动。可见, 肾上腺糖皮质激素与生物钟有着非常密切的关系。文章综述了两者的相互影响并对今后的研究方向做了展望。</P>
URLMagsci [本文引用: 1]
<P>由生物体内源性生物钟所产生的昼夜节律是近年来生命科学的研究热点之一。哺乳动物中的昼夜节律系统由位于下丘脑SCN核内的主钟和位于多数外周细胞中的子钟组成。生物钟基因及其编码的蛋白质组成反馈回路,维持振荡系统持续进行并与环境周期保持同步。光照和食物是生物钟重要的授时因子, 光照刺激能引起肾上腺中基因表达变化以及糖皮质激素的分泌, 而肾上腺糖皮质激素能减缓由食物因子引起的外周生物钟时相的移动。可见, 肾上腺糖皮质激素与生物钟有着非常密切的关系。文章综述了两者的相互影响并对今后的研究方向做了展望。</P>
URLPMID:25016176 [本文引用: 1]
The circadian timekeeping mechanism adapts physiology to the 24-hour light/dark cycle. However, how the outputs of the circadian clock in different peripheral tissues communicate and synchronize each other is still not fully understood. The circadian clock has been implicated in the regulation of numerous processes, including metabolism, the cell cycle, cell differentiation, immune responses, redox homeostasis, and tissue repair. Accordingly, perturbation of the machinery that generates circadian rhythms is associated with metabolic disorders, premature ageing, and various diseases including cancer. Importantly, it is now possible to target circadian rhythms through systemic or local delivery of time cues or compounds. Here, we summarize recent findings in peripheral tissues that link the circadian clock machinery to tissue-specific functions and diseases.
URLPMID:28802040
Abstract Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits. Copyright 漏 2017 Elsevier Inc. All rights reserved.
URLPMID:25485508
Abstract Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.
URLPMID:25099274
Abstract The central circadian clock within the suprachiasmatic nucleus (SCN) plays an important role in temporally organizing and coordinating many of the processes governing cancer cell proliferation and tumor growth in synchrony with the daily light/dark cycle which may contribute to endogenous cancer prevention. Bioenergetic substrates and molecular intermediates required for building tumor biomass each day are derived from both aerobic glycolysis (Warburg effect) and lipid metabolism. Using tissue-isolated human breast cancer xenografts grown in nude rats, we determined that circulating systemic factors in the host and the Warburg effect, linoleic acid uptake/metabolism and growth signaling activities in the tumor are dynamically regulated, coordinated and integrated within circadian time structure over a 24-hour light/dark cycle by SCN-driven nocturnal pineal production of the anticancer hormone melatonin. Dim light at night (LAN)-induced melatonin suppression disrupts this circadian-regulated host/cancer balance among several important cancer preventative signaling mechanisms, leading to hyperglycemia and hyperinsulinemia in the host and runaway aerobic glycolysis, lipid signaling and proliferative activity in the tumor.
URLPMID:26374931
Routine exposure to artificial light at night (ALAN) in work, home, and community settings is linked with increased risk of breast and prostate cancer (BC, PC) in normally sighted women and men, the hypothesized biological rhythm mechanisms being frequent nocturnal melatonin synthesis suppression, circadian time structure (CTS) desynchronization, and sleep/wake cycle disruption with sleep deprivation. ALAN-induced perturbation of the CTS melatonin synchronizer signal is communicated maternally at the very onset of life and after birth via breast or artificial formula feedings. Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like - now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children - is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484鈥塶m 位) spectrum synchronizes the CTS and whose UV-B (290-315鈥塶m 位) spectrum stimulates vitamin D synthesis. Under natural conditions and clear skies, day/night and annual cycles of UV-B irradiation drive corresponding periodicities in vitamin D synthesis and numerous bioprocesses regulated by active metabolites augment and strengthen the biological time structure. Vitamin D insufficiency and deficiency are widespread in children and adults in developed and developing countries as a consequence of inadequate sunlight exposure. Past epidemiologic studies have focused either on exposure to too little daytime UV-B or too much ALAN, respectively, on vitamin D deficiency/insufficiency or melatonin suppression in relation to risk of cancer and other, e.g., psychiatric, hypertensive, cardiac, and vascular, so-called, diseases of civilization. The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in today's man-made artificial light environment, which in our opinion is long overdue.
URLPMID:25900041
Abstract The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address. 脗漏 2015 The Author(s).
URLPMID:2587424 [本文引用: 1]
Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.
URLPMID:20148688 [本文引用: 1]
Abstract The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals. Individual SCN neurons in dispersed culture can generate independent circadian oscillations of clock gene expression and neuronal firing. However, SCN rhythmicity depends on sufficient membrane depolarization and levels of intracellular calcium and cAMP. In the intact SCN, cellular oscillations are synchronized and reinforced by rhythmic synaptic input from other cells, resulting in a reproducible topographic pattern of distinct phases and amplitudes specified by SCN circuit organization. The SCN network synchronizes its component cellular oscillators, reinforces their oscillations, responds to light input by altering their phase distribution, increases their robustness to genetic perturbations, and enhances their precision. Thus, even though individual SCN neurons can be cell-autonomous circadian oscillators, neuronal network properties are integral to normal function of the SCN.
URLPMID:25741730 [本文引用: 1]
Abstract The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, is a network structure composed of multiple types of neurons. Here, we report that mice with a Bmal1 deletion specific to arginine vasopressin (AVP)-producing neurons showed marked lengthening in the free-running period and activity time of behavior rhythms. When exposed to an abrupt 8-hr advance of the light/dark cycle, these mice reentrained faster than control mice did. In these mice, the circadian expression of genes involved in intercellular communications, including Avp, Prokineticin 2, and Rgs16, was drastically reduced in the dorsal SCN, where AVP neurons predominate. In slices, dorsal SCN cells showed attenuated PER2::LUC oscillation with highly variable and lengthened periods. Thus, Bmal1-dependent oscillators of AVP neurons may modulate the coupling of the SCN network, eventually coupling morning and evening behavioral rhythms, by regulating expression of multiple factors important for the network property of these neurons. Copyright 漏 2015 Elsevier Inc. All rights reserved.
