Dopaminergic system dysregulation in the <i>mrsk2</i>_KO mouse, an animal model of the Coffin‐Lowry syndrome

Pereira, Patricia Marques; Gruss, Michael; Braun, Katharina; Foos, Nicolas; Pannetier, Solange; Hanauer, André

doi:10.1111/j.1471-4159.2008.05703.x

Cited by 14 publications

(9 citation statements)

References 45 publications

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“…Western blot analyses were performed as previously described [35]. Thirty μg of protein extracts for each sample were loaded on the SDS-PAGE gel.…”

Section: Methodsmentioning

confidence: 99%

“…Reverse transcription (RT) was performed on 1 μg RNA using the Transcriptor kit (03 531 317 001; Roche Molecular Biochemicals, Indianapolis, IN, USA) to generate cDNA with oligo dT following the manufacturer’s protocol. Real time QRT-PCR was performed with LightCycler480 Sybr Green I Master (Roche SA, Boulogne-Billancourt, France) and achieved using a Light Cycler instrument (Roche) [35]. The sequence of PCR primers used for detection of Rsk2 (Forward 5′-ACAAGGGGTGGTTCACAGAG-3′, Reverse 5′-GCATCATAACCTTGCCGTTT-3′), Gria2 (Forward 5′-TTTCCTTGGGTGCCTTTATG-3′, Reverse 5′-GACAGATCCTCAGCACTTTCG-3′) and Sp1 (Forward 5′-CAGACTCAGTATGTGGACCAA-3′, Reverse 5′-GTTGAATAGCTGTTGGCAT-3′).…”

Section: Methodsmentioning

confidence: 99%

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Rsk2 Knockdown in PC12 Cells Results in Sp1 Dependent Increased Expression of the Gria2 Gene, Encoding the AMPA Receptor Subunit GluR2

Mehmood

Schneider

Pannetier

et al. 2013

IJMS

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The RSK2 protein is a member of the RSK serine-threonine protein kinase family and is encoded by the X-linked rps6ka3 gene in human. Highly heterogeneous loss-of-function mutations affecting this gene are responsible for a severe syndromic form of cognitive impairment, Coffin-Lowry syndrome. RSK2, which is highly conserved in mammals, acts at the distal end of the Ras-ERK signaling pathway and is activated in response to growth factors and neurotransmitters. RSK2 is highly expressed in the hippocampus, and Rsk2-KO mice display spatial learning and memory impairment. We recently showed that ERK1/2 activity is abnormally increased in the hippocampus of Rsk2-KO mice as well as the expression of the AMPA receptor subunit GluR2. The mechanism via which RSK2 deficiency affects the expression of GluR2 in neural cells was unknown. To address this issue we constitutively suppressed the expression of RSK2 in PC12 cells via vector-based shRNA in the present study. We show that Rsk2 silencing leads also to an elevation of ERK1/2 phosphorylation as well as of GluR2 expression and that the increased level of GluR2 expression results from the increased ERK1/2 activity on the transcription factor Sp1. Our results provide evidence that RSK2 modulates ERK1/2 activity on Sp1, which regulates GluR2 expression through transcriptional activation.

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“…Western blot analyses were performed as previously described [35]. Thirty μg of protein extracts for each sample were loaded on the SDS-PAGE gel.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Rsk2 Knockdown in PC12 Cells Results in Sp1 Dependent Increased Expression of the Gria2 Gene, Encoding the AMPA Receptor Subunit GluR2

Mehmood

Schneider

Pannetier

et al. 2013

IJMS

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“…Brains were rapidly dissected and the hippocampus was isolated using a standard dissection procedure. Whole protein extractions were performed as previously described (Marques Pereira et al. 2008).…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analyses were performed as previously described (Marques Pereira et al. 2008), with minor modifications.…”

Section: Methodsmentioning

confidence: 99%

Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin‐Lowry syndrome

Schneider

Mehmood

Pannetier

et al. 2011

Journal of Neurochemistry

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J. Neurochem. (2011) 119, 447–459. Abstract Coffin–Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1–4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal‐regulated kinase (ERK) in the Ras/MAPK signaling pathway. RSK2 is highly expressed in the hippocampus, and mrsk2_KO mice display spatial learning and memory impairment. In the present study, we provide evidence of abnormally increased phosphorylation of ERK1/2 in the hippocampus of mrsk2_KO mice. Further studies based on cultured hippocampal neurons revealed that glutamate activates ERK1/2 and RSKs, and confirmed a stronger activation of ERK1/2 in mrsk2_KO neurons than in WT cells. We, thus, provide further evidence that RSK2 exerts a feedback inhibitory effect on the ERK1/2 pathway. We also observed a transient sequestration of P‐ERK1/2 in the cytoplasm upon glutamate stimulation. In addition, the transcription factors cAMP response element binding and Ets LiKe gene1 show over‐activation in RSK2‐deficient neurons. Finally, c‐Fos, Zif268 and Arc were significantly over‐expressed in mrsk2_KO neurons upon glutamate stimulation. Importantly, the increased phosphorylation of other RSK family members observed in mutant neurons was unable to compensate for RSK2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunction in mrsk2_KO mice and in the Coffin‐Lowry syndrome.

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“…In the dentate gyrus, alterations in the morphology of dendritic spines were observed ( Morice et al, 2013 ). Physiological changes include an increase of cortical dopamine levels, which is accompanied by elevated expression of the dopamine receptor DrD2L ( Pereira et al, 2008 ). In the hippocampus, upregulated expression of the GluR2 subunit of AMPA-type glutamate receptors (GluRs) is correlated with changes in channel properties, synaptic transmission and long-term potentiation-induced gene expression ( Mehmood et al, 2011 ; Morice et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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

Beck

Ehmann

Andlauer

et al. 2015

Disease Models &Amp; Mechanisms

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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.

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Dopaminergic system dysregulation in the mrsk2_KO mouse, an animal model of the Coffin‐Lowry syndrome

Cited by 14 publications

References 45 publications

Rsk2 Knockdown in PC12 Cells Results in Sp1 Dependent Increased Expression of the Gria2 Gene, Encoding the AMPA Receptor Subunit GluR2

Rsk2 Knockdown in PC12 Cells Results in Sp1 Dependent Increased Expression of the Gria2 Gene, Encoding the AMPA Receptor Subunit GluR2

Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin‐Lowry syndrome

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

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