Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostriatal stimulation.
Activity-dependent changes in neuronal structure and synaptic remodeling depend critically on gene regulation. In an attempt to understand how glutamate receptor stimulation at the membrane leads to gene regulation in the nucleus, we traced intracellular signaling pathways targeting DNA regulatory elements of immediate early genes (IEGs). For this purpose we used an in vivo electrical stimulation of the glutamatergic corticostriatal pathway. We show that a transient activation of extracellular signal-regulated kinase (ERK) proteins (detected by immunocytochemistry with an anti-active antibody) is spatially coincident with the onset of IEG induction [c-fos, zif 268, and map kinase phosphatase-1 (MKP-1) detected by in situ hybridization] in the striatum, bilaterally. Both Elk-1 and CREB transcription factors (targeting SRE and CRE DNA regulatory elements, respectively) were hyperphosphorylated in register with ERK activation and IEG mRNA induction. However, their hyperphosphorylation occurred in different subcellular compartments: the cytoplasm and the nucleus for Elk-1 and the nucleus for CREB. The role of the ERK signaling cascade in gene regulation was confirmed after intrastriatal and unilateral injection of the specific ERK inhibitor PD 98059, which completely abolished c-fos, zif 268, and MKP-1 mRNA induction in the injected side. Of interest, both Elk-1 and CREB hyperphosphorylation also was impaired after PD 98059 injection. Thus two different ERK modules, one depending on the cytoplasmic activation of Elk-1 and the other one depending on the nuclear activation of CREB, control IEG transcriptional regulation in our model. Our findings provide significant insights into intracellular mechanisms underlying synaptic plasticity in the striatum.
Sgambato
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Laboratoire Neurochimie-Anatomie, Institut des Neurosciences, Unité Mixte de Recherche 7624, Université Pierre et Marie Curie, 75005 Paris, France.
Pagès
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Rogard
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Besson
M J
MJ
Caboche
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D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D051766:Early Growth Response Protein 1; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000235:genetics*; D017874:Immediate-Early Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017774:Long-Term Potentiation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009044:Motor Cortex / Q000502:physiology*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1
D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017874:Immediate-Early Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one