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

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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.