The impact of protein kinase RSK on circadian clock modulation, neuronal plasticity and behavioral timing in Drosophila.

丝裂原活化蛋白激酶（MAPK） ERK是调节多种细胞内功能的同名信号通路的一个组成部分。虽然ERK通常与细胞增殖、分化和凋亡有关，但它也调节许多其他过程，包括神经元和昼夜节律机制。因此，ERK信号的失调不仅在肿瘤发生中起着重要作用，而且在神经元功能障碍和神经精神疾病中也起着重要作用。RSK蛋白作为ERK的几个下游介质之一，在神经系统中具有明显的多效性，但仍然知之甚少。不幸的是，我们对导致人类rsk2突变（coffin - lowry综合征）导致严重精神残疾的病理生理学知识的缺乏说明了这一点。本应用程序旨在解剖黑腹果蝇的神经元RSK功能，使用昼夜节律系统作为一个非常有特征的实验模型。时钟网络非常适合于综合方法，因为它允许在分子水平上分析RSK功能，研究其对细胞/生理过程的影响，并评估其对行为的影响。基于我们之前的发现，我们将首先扩展我们对RSK作为分子昼夜节律振荡器调节器的分析。其次，有希望的初步实验支持RSK作为时钟神经元（s-LNv）亚类背端昼夜形态可塑性的调节性。结合我们之前在果蝇运动神经元系统中的发现，RSK功能与突触特性和这些末端的ERK信号传导有关的问题出现了。RSK功能的丧失是否会改变s-LNv连接，这是否与时间依赖性行为反应的变化有关？这个应用程序的第三个重点是建立在我们最近发现的RSK在恐惧行为中的功能。我们的目标是剖析rsk依赖的神经回路和恐惧样行为的昼夜节律调节，并确定g蛋白偶联受体信号的rsk依赖调节在多大程度上参与其中。鉴于果蝇和人类在神经化学和分子通路上的相似性，在拟议的果蝇项目中发现的RSK功能不仅可能为哺乳动物的RSK功能提供蓝图，而且可能有助于理解coffin - lowry综合征的复杂病理生理。

The mitogen activated protein kinase (MAPK) ERK is a component of the eponymous signaling pathway that regulates various intracellular functions. Though typically associated with cell proliferation, differentiation and apoptosis, ERK also regulates many other processes, including neuronal and circadian mechanisms. Consequently, deregulation of ERK signaling does not only play a prominent role in tumorigenesis, but also in neuronal dysfunction and neuropsychiatric disorders.RSK proteins act as one out of several downstream mediators of ERK with apparently pleiotropic - but still poorly understood- functions in the nervous system. This is unfortunately illustrated by our lack of knowledge in pathophysiology leading to severe mental disabilities caused by rsk2 mutations in humans (Coffin-Lowry-Syndrome). This application aims to dissect neuronal RSK functions in Drosophila melanogaster, using the circadian system as a very well characterized experimental model. The clock network is ideally suited for an integrative approach because it allows analysis of RSK function at the molecular level, to study its impact on cellular/physiological processes and to evaluate its influence on behaviors. Based on our previous findings, we will first extend our analysis of RSK as a regulator of the molecular circadian oscillator. Second, promising first experiments support a function of RSK as a modulator of diurnal morphological plasticity of the dorsal terminals of a subclass of clock neurons (s-LNv). In combination with our previous findings in the motoneuron system of the fly, the question of RSK function in relation to synaptic properties and ERK signaling at these terminals arises. Does loss of RSK function alter s-LNv connectivity, and does this correlate with changes in time-dependent behavioral responses? A third focus of this application builds on our recent discovery of RSK function in fear-like behavior. We aim to dissect the RSK-dependent neural circuitry and the circadian modulation of fear-like behavior, and we will determine to which degree RSK-dependent modulation of G-protein coupled receptor signaling is involved. Given the similarities in neurochemical and molecular pathways between flies and humans, functions of RSK uncovered within the proposed fly project may not only provide a blueprint for RSK functions in mammals, but may also help to understand the complex pathophysiology of Coffin-Lowry-Syndrome.