title: Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons.
abstract: 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.
authors.affiliation: University of Würzburg, Institute of Medical Radiation and Cell Research, Versbacherstraße 5, Würzburg D-97078, Germany.
authors.forename: Katherina
authors.initials: K
authors.lastname: Beck
authors.affiliation: University of Würzburg, Institute of Physiology, Department of Neurophysiology, Röntgenring 9, Würzburg D-97070, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Ehmann
authors.affiliation: University of Würzburg, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Josef-Schneider-Straße 2, Würzburg D-97080, Germany Freie Universität Berlin, Institute of Biology, Takusstraße 6, Berlin D-14195, Germany Max Planck Institute of Colloidals and Interfaces, Am Mühlenberg 1, Potsdam D-14476, Germany.
authors.forename: Till F M
authors.initials: TF
authors.lastname: Andlauer
authors.affiliation: University of Würzburg, Institute of Physiology, Department of Neurophysiology, Röntgenring 9, Würzburg D-97070, Germany.
authors.forename: Dmitrij
authors.initials: D
authors.lastname: Ljaschenko
authors.affiliation: University of Würzburg, Institute of Medical Radiation and Cell Research, Versbacherstraße 5, Würzburg D-97078, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Strecker
authors.affiliation: University Hospital Würzburg, Department of Psychiatry, Psychosomatics and Psychotherapy, Füchsleinstraße 15, Würzburg 97080, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: University of Würzburg, Institute of Physiology, Department of Neurophysiology, Röntgenring 9, Würzburg D-97070, Germany.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kittel
authors.affiliation: University of Würzburg, Institute of Medical Radiation and Cell Research, Versbacherstraße 5, Würzburg D-97078, Germany thomas.raabe@mail.uni-wuerzburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Raabe
mesh_terms: D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000201:enzymology* / Q000473:pathology; D038921:Coffin-Lowry Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D055369:Miniature Postsynaptic Potentials; D008928:Mitochondria / Q000201:enzymology; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009469:Neuromuscular Junction / Q000201:enzymology* / Q000473:pathology; D009473:Neuronal Plasticity; D010641:Phenotype; D017729:Presynaptic Terminals / Q000201:enzymology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D013997:Time Factors
chemical_list: D029721:Drosophila Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Axonal transport; Drosophila; MAPK signaling; Motoneuron; Neuromuscular junction; RSK; Synapse