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首页> 外文期刊>Chronobiology international >Constitutive activation of ras in neurons: Implications for the regulation of the mammalian circadian clock
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Constitutive activation of ras in neurons: Implications for the regulation of the mammalian circadian clock

机译：ras在神经元中的组成性激活：对哺乳动物昼夜节律的调节意义。

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Almost all organisms living on earth exhibit rhythms under the control of autonomous timekeeping mechanisms referred to as circadian clocks. In mammals, peripheral clocks are synchronized (entrained) with high precision in a 24 h periodicity by the master circadian clock located in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus. Light is the strongest phase-adjusting stimulus of the circadian clock. Circadian oscillations are driven by transcription/translation-based feedback/feedforward loops, comprising a set of clock genes and their protein products. The signalling pathways that couple light input to transcriptional, translational, and post-translational changes to ensure precise entrainment of the clock are not yet well characterized. A candidate pathway for transmission of photic information in the SCN is represented by the extracellular signal-regulated kinases ERK1/ERK2. In neurons, the ERK pathway is activated by a large array of stimuli, including trophic factors, neurotransmitters, and modulatory peptides. An upstream element of the ERK signalling route is the small intracellular membrane-anchored G-protein, Ras. In order to study its possible role in the entrainment of the circadian clock we are using transgenic gain-of-function mice expressing constitutively activated Val-12 Ha-Ras selectively in neurons (synRas mice). The Ha-Ras transgene protein is expressed in the SCN of synRas mice neurons serving as a model for interfering with the normal rhythmic changes in Ras activities in the SCN. This will allow us to investigate whether the associated modulation of the downstream targets such as ERK activities will interfere with the mechanisms of entrainment.
机译：在被称为生物钟的自主计时机制的控制下，几乎所有生活在地球上的生物都表现出节律。在哺乳动物中，外围时钟通过位于腹下丘脑上睑上核（SCN）的主生物钟在24小时内以高精度同步（夹带）。光是生物钟最强的相位调整刺激。昼夜节律振荡由基于转录/翻译的反馈/前馈环驱动，该环包括一组时钟基因及其蛋白质产物。将光输入耦合到转录，翻译和翻译后变化以确保精确夹带时钟的信号传导途径尚未很好地表征。 SCN中光信息传递的候选途径由细胞外信号调节激酶ERK1 / ERK2代表。在神经元中，ERK途径被一系列刺激（包括营养因子，神经递质和调节肽）激活。 ERK信号传导途径的上游元素是小细胞内膜锚定的G蛋白Ras。为了研究其在昼夜节律的夹带中的可能作用，我们使用了在神经元中选择性表达组成型激活的Val-12 Ha-Ras的转基因功能小鼠（synRas小鼠）。 Ha-Ras转基因蛋白在synRas小鼠神经元的SCN中表达，可作为模型来干扰SCN中Ras活性的正常节律变化。这将使我们能够调查下游目标（如ERK活动）的相关调节是否会干扰夹带机制。

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