Defining the molecular basis of photperiodism in mammals

定义哺乳动物光周期现象的分子基础

• 批准号: BB/E017193/1
• 负责人: David Hazelrigg
• 金额: $ 49.51万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE017193%2F1
• 关键词: Defining; molecular; basis; photperiodism; mammals

The perpetual motion of the Earth on its axis and the orbit around the sun generates a rhythmic environment for life on Earth. Organisms of all types have responded by evolving biological clocks and calendars that allow anticipation of day and night, and the changing seasons. Recent research into this 'chronobiology' has characterised a small number of genes, called clock genes, which generate the intrinsic daily rhythm. These genes show conserved features in their structure and function from insects to man, reflecting their ancient evolution. Clock genes act within most cells of the body to produce a near 24-hour rhythmic output, and cells communicate to regulate daily rhythms in sleep-activity, feeding, hormone secretion and many other characteristics. Much less is understood about the molecular basis of longer-term timers and the mechanism by which animals respond to changing day length to synchronise seasonal rhythms. In mammals, a key aspect of seasonal timekeeping is the production of melatonin by the pineal gland. Melatonin is produced only at night and the pattern directly reflects the length of the night, and it is the changes in this hormonal signal that conveys information about time of year around the body. Long daily bouts of melatonin act as the signal for winter and short bouts for summer. Our previous work has shown that the changing pattern of melatonin is decoded through the switching on and off of specific clock genes. Notably, the melatonin increase at dusk activates Cry1 gene expression, and the melatonin decline at dawn activates Per1 gene expression. Based on this we have proposed an 'internal coincidence hypothesis' for photoperiod time measurement. This states that the extent of interaction between CRY1 and PER1 proteins, which is dictated by the period from dusk to dawn - the melatonin signal, governs the seasonal response. The daily clock mechanism has thus been co-opted for seasonal timing in melatonin-responsive cells that are located in the brain and pituitary gland. Now we plan to test this hypothesis using transgenic sheep in which the Cry1 gene is selectively neutralised. This strategy depends on our recent demonstration that modified DNA sequences can be efficiently introduced into sheep embryos and are expressed in lambs. The sheep is used as a model because of its very well characterised seasonal biology. The aim is to use two different 'transgenes' to interfere with endogenous expression of the Cry1 gene. The prediction is that this will not affect normal development, but will block photoperiodic responsiveness. The biology of this 'sheep for all seasons' will be of major interest to chronobiologists, and the use of transgenesis in sheep opens a new era in the study of genetic control in a long-lived species.

地球在其轴上的永恒运动和围绕太阳的轨道为地球上的生命创造了一个有节奏的环境。所有类型的生物体都通过进化生物钟和日历来做出反应，这些生物钟和日历允许对白天和黑夜以及季节变化进行预测。最近对这种“时间生物学”的研究已经确定了一小部分基因的特征，称为时钟基因，它们产生内在的日常节奏。从昆虫到人类，这些基因在结构和功能上表现出保守的特征，反映了它们的古老进化。生物钟基因在身体的大多数细胞中起作用，产生近24小时的有节奏的输出，细胞通过交流来调节睡眠活动、进食、激素分泌和许多其他特征的日常节奏。关于长期计时器的分子基础以及动物对改变白昼长度以同步季节节律的机制，人们了解得更少。在哺乳动物中，季节性计时的一个关键方面是松果体产生褪黑激素。褪黑激素只在晚上产生，其模式直接反映了夜晚的长度，正是这种激素信号的变化传达了身体周围一年中的时间信息。每天长时间的褪黑激素发作是冬天的信号，而夏天的短时间发作是夏天的信号。我们以前的工作表明，褪黑激素的变化模式是通过打开和关闭特定的时钟基因来解码的。值得注意的是，褪黑激素在黄昏时增加激活Cry 1基因表达，褪黑激素在黎明时下降激活Per 1基因表达。在此基础上，我们提出了光周期时间测量的“内部符合假说”。这表明，从黄昏到黎明的时间段-褪黑激素信号-决定了PER 1和PER 1蛋白之间的相互作用程度，决定了季节性反应。因此，位于大脑和脑垂体中的褪黑激素反应细胞的日常时钟机制被选为季节性时间。现在，我们计划使用转基因绵羊来验证这一假设，其中Cry 1基因被选择性地中和。这一策略依赖于我们最近的证明，即修饰的DNA序列可以有效地引入绵羊胚胎并在羔羊中表达。绵羊被用作模型，因为它具有非常好的季节性生物学特征。目的是使用两种不同的“转基因”来干扰Cry 1基因的内源性表达。预测这不会影响正常发育，但会阻断光周期反应。这种“四季皆宜的绵羊”的生物学特性将引起时间生物学家的极大兴趣，在绵羊中使用转基因技术开辟了一个研究长寿物种遗传控制的新时代。