Abstract
ABSTRACTPlastic 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.
Highlights
The p90 ribosomal S6 kinases (RSKs) are a family of serinethreonine kinases that act as downstream effectors of the RASmitogen-activated protein kinase (MAPK) pathway through direct interaction with the extracellular-signal-regulated kinase (ERK)
A major challenge will be to distinguish the ambivalent functions of Ribosomal S6 kinase 2 (RSK2) both as a downstream mediator and as a negative regulator of MAPK signaling in these processes, and to explore potential differential effects on local MAPK signaling
Survival of isolated spinal motoneurons from RSK2-deficient mice was not RESULTS Presynaptic localization of RSK Based on previous genetic studies, which implicated a function of Drosophila RSK in motoneurons (Fischer et al, 2009b), we first determined the subcellular localization of RSK
Summary
The p90 ribosomal S6 kinases (RSKs) are a family of serinethreonine kinases that act as downstream effectors of the RASmitogen-activated protein kinase (MAPK) pathway through direct interaction with the extracellular-signal-regulated kinase (ERK). In this way, RSK proteins link MAPK signaling to a multitude of substrate proteins. In Drosophila melanogaster and in other invertebrates, only a single RSK isoform is expressed. The overall sequence conservation of Drosophila RSK to vertebrate RSK proteins shows no preference for a single isoform and is mainly restricted to the known functional domains
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