Adult circadian behavior in Drosophila requires developmental expression of cycle, but not period.
Adult circadian behavior in Drosophila requires developmental expression of cycle, but not period.
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DOI：
10.1371/journal.pgen.1002167
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Wijnen H
中科院分区：
文献类型：
--
作者：
Goda T;Mirowska K;Currie J;Kim MH;Rao NV;Bonilla G;Wijnen H
昼夜节律钟已经进化为内部时间保持机制，其允许预测每日环境变化并组织生理和行为节律的每日程序。为了更好地研究动物生物钟的机制，并询问发育过程中时钟基因的表达和功能是否会影响成年人随后的日常时间保持，我们使用果蝇中可用的遗传工具来有条件地操纵正调节器时钟/周期（CLK/CYC）或其负反馈抑制剂周期（PER）的周期成分的功能。在发展过程中和成年期的差异操纵时钟功能表明，没有发展的要求，无论是一个运行的时钟机制或表达的每。然而，有条件的抑制CLK/CYC活性，无论是通过每过度表达或CYC消耗在变态过程中导致持续的成虫的行为。确定了两种不同的机制，可能有助于CLK/CYC的这种发育功能，并且都涉及对运动行为的昼夜节律控制至关重要的腹侧时钟神经元（LNvs）：（1）选择性去除LNv中cyc表达导致异常的肽能小LNv背侧投射，（2）CLK/CYC活性的发育抑制可能影响LNvs的PER表达节律。鉴于动物之间的时钟基因和电路的保护，这项研究提供了一个合理的调查同源哺乳动物CLOCK/BMAL1复合物可能类似的发展作用。果蝇Drosophila melanogaster是研究动物用于日常时间保持的内部生物钟的极好模型系统。由于生物钟不仅存在于成年动物体内，而且在早期发育过程中也发挥作用，因此出现了一个问题，即成年人的昼夜节律是否以及如何依赖于发育中的生物钟电路和组件。为了解决这个问题，我们创造了转基因果蝇，其中基本的时钟组件时钟/周期（CLK/CYC）和周期（PER）可以通过环境温度来操纵。在发育过程中，通过消耗负调节因子PER来停止生物钟并不能阻止成年人恢复昼夜节律时间。然而，由于正调节因子CYC的耗尽或PER的过度产生导致的时钟发育停滞导致了成年人时钟控制行为功能的持续丧失。综上所述，这些观察结果表明，成人时钟功能发育需要的CLK/CYC转录复合物的活动，而不是滴答作响的时钟。基于抑制时钟/CYC在昼夜节律起搏神经元的行为，分子和解剖学后果，我们建议，发展的要求映射到这些细胞。确定人类的等效时钟基因是否存在类似的发育要求将会很有趣。
Circadian clocks have evolved as internal time keeping mechanisms that allow anticipation of daily environmental changes and organization of a daily program of physiological and behavioral rhythms. To better examine the mechanisms underlying circadian clocks in animals and to ask whether clock gene expression and function during development affected subsequent daily time keeping in the adult, we used the genetic tools available in Drosophila to conditionally manipulate the function of the CYCLE component of the positive regulator CLOCK/CYCLE (CLK/CYC) or its negative feedback inhibitor PERIOD (PER). Differential manipulation of clock function during development and in adulthood indicated that there is no developmental requirement for either a running clock mechanism or expression of per. However, conditional suppression of CLK/CYC activity either via per over-expression or cyc depletion during metamorphosis resulted in persistent arrhythmic behavior in the adult. Two distinct mechanisms were identified that may contribute to this developmental function of CLK/CYC and both involve the ventral lateral clock neurons (LNvs) that are crucial to circadian control of locomotor behavior: (1) selective depletion of cyc expression in the LNvs resulted in abnormal peptidergic small-LNv dorsal projections, and (2) PER expression rhythms in the adult LNvs appeared to be affected by developmental inhibition of CLK/CYC activity. Given the conservation of clock genes and circuits among animals, this study provides a rationale for investigating a possible similar developmental role of the homologous mammalian CLOCK/BMAL1 complex. The fruit fly Drosophila melanogaster is an excellent model system for studying the internal circadian clocks that animals use for daily time keeping. Since clocks exist and function in animals not only in adults, but also during prior development, the question arises if and how adult circadian rhythms depend on developmental clock circuits and components. To address this question we created transgenic flies in which the essential clock components CLOCK/CYCLE (CLK/CYC) and PERIOD (PER) can be manipulated via environmental temperature. Stopping the clock during development by depleting the negative regulator PER did not prevent restoration of circadian time keeping in the adult. However, a developmental arrest of the clock due to either depletion of the positive regulator CYC or overproduction of PER resulted in a persistent loss of clock-controlled behavior function in adults. Taken together, these observations indicate that adult clock function developmentally requires activity of the CLK/CYC transcription complex rather than a ticking clock. Based on the behavioral, molecular, and anatomical consequences of inhibiting CLK/CYC in circadian pacemaker neurons, we propose that the developmental requirement maps to these cells. It will be interesting to determine whether there is a comparable developmental requirement for the equivalent clock genes in humans.
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