Abstract
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.
Highlights
Coffin-Lowry syndrome (CLS, OMIM 303600) is a rare X-chromosome linked disorder with an incidence of 1:50,000–100,000
We summarize findings with both animal models and their implications to better understand the neuropathophysiology of CLS
In comparison to wild-type, spatial memory recall in ribosomal S6 kinase 2 (RSK2)− mice activated less newborn neurons but more pre-existing neurons (Castillon et al, 2018; Figure 2). These experiments provided first evidence that altered adult neurogenesis can contribute to the behavioral phenotypes seen in RSK2− mice in a context-dependent manner
Summary
Coffin-Lowry syndrome (CLS, OMIM 303600) is a rare X-chromosome linked disorder with an incidence of 1:50,000–100,000. Animal Models for Coffin-Lowry Sydrome knock-out mice (RSK2−) and mutants of the single RSK ortholog in Drosophila (D-RSK) were analyzed at the behavioral and neurophysiological level. Up-regulation of ERK activity has been verified in the hippocampus and motoneurons of RSK2− mice (Fischer et al, 2009a; Schneider et al, 2011) as well as in larval motoneurons and adult brains of D-RSK mutants (Fischer et al, 2009b; Beck et al, 2015).
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