BioProject

Analysis of alterations in the hippocampus transcriptome caused by deletion of Mitogen Stress activated Kinase 1 (MSK1). More...

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. Overall design: We profiled total RNA from bilateral hippocampal tissue obtained from 6 mice, corresponding to 3 animals per genotype (wild type and MSK1 null) using the GeneChip 430A 2.0 Mouse Genome Array. Raw data (.cel files) were processed using dChip software (http://www.hsph.harvard.edu/cli/complab/dchip/). Less...