MSK1 is required for the beneficial synaptic and cognitive effects of enriched experience across the lifespan
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA984238 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24935030_1.fastq.gz | Fastqsanger.gz | |||
| SRR24935030_2.fastq.gz | Fastqsanger.gz | |||
| SRR24935032_1.fastq.gz | Fastqsanger.gz | |||
| SRR24935032_2.fastq.gz | Fastqsanger.gz | |||
| SRR24935034_1.fastq.gz | Fastqsanger.gz |
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Project description:Positive experiences, such as social interaction, cognitive training and physical exercise, have been shown to ameliorate some of the harms to cognition associated with ageing. Animal models of positive interventions, commonly known as environmental enrichment, strongly influence neuronal morphology and synaptic function and enhance cognitive performance. While the profound structural and functional benefits of enrichment have been appreciated for decades, little is known as to how the environment influences neurons to respond and adapt to these positive sensory experiences. We show that adult and aged male wild-type mice that underwent a 10-week environmental enrichment protocol demonstrated improved performance in a variety of behavioural tasks, including those testing spatial working and spatial reference memory, and an enhancement in hippocampal LTP. Aged animals in particular benefitted from enrichment, performing spatial memory tasks at levels similar to healthy adult mice. Many of these benefits, including in gene expression, were absent in mice with a mutation in an enzyme, MSK1, which is activated by BDNF, a growth factor implicated in rodent and human cognition. We conclude that enrichment is beneficial across the lifespan and that MSK1 is required for the full extent of these experience-induced improvements of cognitive abilities, synaptic plasticity and gene expression.
2023-06-20 | GSE235037 | GEO
Project description:Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this we have used male mice harbouring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a BDNF-activated enzyme downstream of the MAPK pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal LTP and LTD, and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function and cognition.
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Project description:Experience recruits MSK1 to expand the dynamic range of synapses and enhance cognition
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Project description:Analysis of alterations in the hippocampus transcriptome caused by deletion of Mitogen Stress activated Kinase 1 (MSK1). MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults. MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults.
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Project description:For many breast cancer (BCa) patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometastatic lesions remain dormant and undetectable yet initiate colonization, are major questions in cancer research. Here we identify and functionally analyse a molecular mechanism involved in bone metastatic latency of estrogen receptor–positive (ER)+ BCa. We developed an in vivo loss-of-function, genome-wide shRNA screening to identify genes relevant for long-latent relapse in BCa. This screen revealed the kinase MSK1 as an important regulator of metastatic dormancy. Importantly, low MSK1 expression associates with early metastasis in ER+ BCa patients. Reduced MSK1 levels impaired cellular differentiation and increased the bone homing and growth capacity of metastatic cells. MSK1 modulates chromatin status at promoters to regulate the expression of luminal differentiation genes, including those for the GATA-3 and FOXA1 transcription factors, which prevent the progression of ER+ BCa towards metastasis. Our results identify the regulation of luminal cell differentiation by MSK1 via modulation of chromatin remodelling to be a key mechanism for controlling metastatic dormancy in BCa. We propose that MSK1 could be a useful marker for stratifying BCa patients as high- or low-risk for early relapse, allowing patients to receive appropriate treatments.
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Project description:Here, we used conditional cell-specific gene targeting in mice with multi-omics approaches, and demonstrated that the RhoGTPase Rac1 was an essential requirement for the microglia to sense and interpret the brain microenvironment, and for crucial microglia-synapse crosstalk driving experience-dependent plasticity. Phosphoproteomics profiling detected a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol. Ablation of microglial Rac1 affected pathways involved in microglia-synapse communication, disrupted experience-dependent synaptic remodeling, and blocked the gains in learning, memory and sociability induced by environmental enrichment.
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Project description:The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following 4 different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3,938 proteins and 2,761 phosphoproteins in the sequential strategy covering a total of 4,968 unique protein groups (at least 2 peptides including an unique peptide). On the phosphoproteins, we identified a total of 6,188 unambiguous phosphosites (75% site localization probability)
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, HOXC6, is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mTOR pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth due to its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated IGF1R signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, HOXC6, is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mTOR pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth due to its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated IGF1R signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.
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