Loss of the Coffin-Lowry syndrome associated gene<i>RSK2</i>alters ERK activity, synaptic function and axonal transport in<i>Drosophila</i>motoneurons

Beck, Katherina; Ehmann, Nadine; Andlauer, Till F. M.; Ljaschenko, Dmitrij; Strecker, Katrin; Fischer, Matthias; Kittel, Robert J.; Raabe, Thomas

doi:10.1242/dmm.021246

Cited by 17 publications

(16 citation statements)

References 60 publications

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“…This syndrome is characterized by tall stature, craniofacial defects and mental retardation. Loss of function in human ribosomal S6 kinase 2 (RSK2) causes Coffin-Lowry syndrome, an X-linked disorder characterized by severe mental retardation in males (Beck et al, 2015). RSK2 acts as a regulator of ERK signaling, which may impact cell proliferation and differentiation during brain development.…”

Section: Open-loop Mechanismsmentioning

confidence: 99%

Outstanding questions in developmental ERK signaling

Patel

Shvartsman

2018

Development

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The extracellular signal-regulated kinase (ERK) pathway leads to activation of the effector molecule ERK, which controls downstream responses by phosphorylating a variety of substrates, including transcription factors. Crucial insights into the regulation and function of this pathway came from studying embryos in which specific phenotypes arise from aberrant ERK activation. Despite decades of research, several important questions remain to be addressed for deeper understanding of this highly conserved signaling system and its function. Answering these questions will require quantifying the first steps of pathway activation, elucidating the mechanisms of transcriptional interpretation and measuring the quantitative limits of ERK signaling within which the system must operate to avoid developmental defects.

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Section: Open-loop Mechanismsmentioning

confidence: 99%

Outstanding questions in developmental ERK signaling

Patel

Shvartsman

2018

Development

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“…ders share similar craniofacial features, which makes it challenging to pinpoint the causative gene. Upregulating the ras-MAPK pathway due to loss of function in RPS6KA3 may be related to the similar craniofacial features and mental retardation like in Noonan syndrome 21,22. A previous report also described the experience of misdiagnosis of CLS as Noonan syndrome; the authors identified an RPS6KA3 gene mutation through WES.…”

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confidence: 94%

“…3 The RPS6KA3 gene encodes a growth factor at the downstream end of the ras-mitogen-activated protein kinase (MAPK) pathway, regulating the serine-threonine kinase.Ribosomal Protein S6 Kinase A3 (RPS6KA3) is directly activated by the extracellular signal kinase (ERK) in response to a range of stimuli, including the growth part of a gene family implicated in cellcycle regulation through the MAPK cascade 20. Upregulating the ras-MAPK pathway due to loss of function in RPS6KA3 may be related to the similar craniofacial features and mental retardation like in Noonan syndrome 21,22. Although CLS is an X-linked dominant disorder, various intellectual deficit in female carriers can be explained by skewed X-chromosome inactivation in the brain which may not be consistent with the status of the X-chromosome in peripheral blood or other tissue 20.…”

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confidence: 99%

High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing

et al. 2017

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“…Basal synaptic transmission was not affected by RSK inhibition or RSK siRNA. This last result does contrast with the effect of constitutive rsk knockout in mouse (reduction of basal synaptic transmission induced by knockout of rsk2 8 ), and in Drosophila (requirement of a RSK orthologue for normal synaptic morphology and function 23 ). This could be due to the transient (only a few days) and partial knockdown of RSK (Fig.…”

Section: Discussionmentioning

confidence: 85%

Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability

Liu¹,

Zhang²,

Smolen³

et al. 2020

Sci Rep

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Multiple kinases converge on the transcription factor cAMP response element-binding protein (CREB) to enhance the expression of proteins essential for long-term synaptic plasticity and memory. The p90 ribosomal S6 kinase (RSK) is one of these kinases, although its role is poorly understood. The present study exploited the technical advantages of the Aplysia sensorimotor culture system to examine the role of RSK in long-term synaptic facilitation (LTF) and long-term enhancement of neuronal excitability (LTEE), two correlates of long-term memory (LTM). Inhibition of RSK expression or RSK activity both significantly reduced CREB1 phosphorylation, LTF, and LTEE, suggesting RSK is required for learningrelated synaptic plasticity and enhancement in neuronal excitability. In addition, knock down of RSK by RNAi in Aplysia sensory neurons impairs LTF, suggesting that this may be a useful single-cell system to study aspects of defective synaptic plasticity in Coffin-Lowry Syndrome (CLS), a cognitive disorder that is caused by mutations in rsk2 and associated with deficits in learning and memory. We found that the impairments in LTF and LTEE can be rescued by a computationally designed spaced training protocol, which was previously demonstrated to augment normal LTF and LTM. In mammals, gene deletion studies have shown an essential role for the rsk2 gene in cognitive functions 1. In several animal models, the p90 isoform of RSK, expressed from rsk2, phosphorylates (i.e., activates) CREB after activation by the ERK isoform of MAP kinase (MAPK) 2-6. Coffin-Lowry Syndrome (CLS) is caused by X-linked mutations in rsk2, and is associated with human intellectual disability and skeletal abnormalities 7. A mouse rsk2-null model is deficient in fear memory consolidation and stimulus-induced CREB phosphorylation 1,8. CREB-mediated transcription is required for memory formation in vertebrates and invertebrates. In mammalian systems, many of the signaling pathways that lead to phosphorylation of CREB have been well characterized, including the cAMP/PKA pathway and the Ras/ERK pathway 9. However, the potential ERK/RSK/CREB pathway has received little attention as a potential contributor to synaptic plasticity, including long-term potentiation (LTP) and long-term synaptic facilitation (LTF), and also to long-term enhancement of neuronal excitability (LTEE). LTP, LTF, and LTEE are known correlates of long-term memory (LTM). To our knowledge, no study so far has examined the effects of RSK inhibitors on synaptic plasticity or excitability. One study examined the role of RSK2 in LTP using a RSK2 mutant mouse 8. A negative result was reported-LTP was normal in the mutant. The negative result may be explained by the effects of RSK activation not being expressed during the period of observation (120 minutes), or a different isoform of RSK may have compensated for the mutant. Consequently, the role of RSK in long-term synaptic plasticity and enhancement of excitability remains unsettled. The present study exploited advantages of the Aplysia sen...

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Loss of the Coffin-Lowry syndrome associated geneRSK2alters ERK activity, synaptic function and axonal transport inDrosophilamotoneurons

Cited by 17 publications

References 60 publications

Outstanding questions in developmental ERK signaling

Outstanding questions in developmental ERK signaling

High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing

Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability

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