Department of Biology, University of Virginia, Charlottesville, VA, USA.
PLoS Genet. 2011 Jul;7(7):e1002167. doi: 10.1371/journal.pgen.1002167. Epub 2011 Jul 7.
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 (LN(v)s) that are crucial to circadian control of locomotor behavior: (1) selective depletion of cyc expression in the LN(v)s resulted in abnormal peptidergic small-LN(v) dorsal projections, and (2) PER expression rhythms in the adult LN(v)s 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.
生物钟已经进化为内部计时机制，允许动物预测日常环境变化，并组织生理和行为节律的日常程序。为了更好地研究动物生物钟的机制，并探讨发育过程中时钟基因的表达和功能是否会影响成年后的日常时间保持，我们利用果蝇中可用的遗传工具来条件性地操纵正调控 CLOCK/CYCLE（CLK/CYC）的 CYCLE 成分或其负反馈抑制剂 PERIOD（PER）的功能。在发育和成年期间对时钟功能的差异操作表明，无论是运行时钟机制还是 per 的表达，都没有发育要求。然而，在变态期间通过 per 过表达或 cyc 耗竭对 CLK/CYC 活性进行条件抑制，导致成年后持续的节律异常行为。确定了两种可能对 CLK/CYC 的这种发育功能有贡献的机制，它们都涉及到对运动行为进行生物钟控制的腹外侧时钟神经元（LN(v)s）：（1）选择性地在 LN(v)s 中耗竭 cyc 表达导致异常的肽能小-LN(v)背侧投射，（2）成年 LN(v)s 中的 PER 表达节律似乎受到 CLK/CYC 活性发育抑制的影响。鉴于时钟基因和电路在动物中的保守性，这项研究为研究同源哺乳动物 CLOCK/BMAL1 复合物可能具有的类似发育作用提供了依据。
