TY - JOUR A1 - Fischer, Matthias A1 - Raabe, Thomas T1 - Animal models for Coffin-Lowry syndrome: RSK2 and nervous system dysfunction JF - Frontiers in Behavioral Neuroscience N2 - Loss of function mutations in the rsk2 gene cause Coffin-Lowry syndrome (CLS), which is associated with multiple symptoms including severe mental disabilities. Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies. KW - Coffin-Lowry syndrome KW - RSK2 KW - mental disorders KW - mouse model KW - Drosophila model KW - neuronal dysfunction KW - behavior Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176799 VL - 12 IS - 106 ER - TY - JOUR A1 - Beck, Katherina A1 - Ehmann, Nadine A1 - Andlauer, Till F. M. A1 - Ljaschenko, Dmitrij A1 - Strecker, Katrin A1 - Fischer, Matthias A1 - Kittel, Robert J. A1 - Raabe, Thomas T1 - Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons JF - Disease Models & Mechanisms N2 - Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling. KW - mrsk2 KO mouse KW - S6KII RSK KW - transmission KW - neuromuscular junction KW - synapse KW - MAPK signaling KW - axonal transport KW - motoneuron KW - RSK KW - Drosophila KW - mechanisms KW - plasticity KW - protein kinase KW - signal transduction pathway KW - mitochondrial transport KW - glutamate receptor Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145185 VL - 8 ER -