A Genome-Wide Screen of CREB Occupancy Identifies the RhoA Inhibitors Par6C and Rnd3 as Regulators of BDNF-Induced Synaptogenesis
| العنوان: | A Genome-Wide Screen of CREB Occupancy Identifies the RhoA Inhibitors Par6C and Rnd3 as Regulators of BDNF-Induced Synaptogenesis |
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| المؤلفون: | Talley J. Lambert, Monika A. Davare, Suzanne M. Appleyard, Carl Pelz, Karl Obrietan, Mingyan Zhu, Gary A. Wayman, Soren Impey, Hideaki Ando, Katelin F. Hansen, Adam Lesiak |
| المصدر: | PLoS ONE, Vol 8, Iss 6, p e64658 (2013) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | rho GTP-Binding Proteins, Dendritic spine, RHOA, Synaptogenesis, Gene Expression, lcsh:Medicine, Signal transduction, ERK signaling cascade, Hippocampus, Rats, Sprague-Dawley, Molecular cell biology, 0302 clinical medicine, Neurotrophic factors, Protein Isoforms, Membrane Receptor Signaling, Cyclic AMP Response Element-Binding Protein, Promoter Regions, Genetic, lcsh:Science, Cells, Cultured, Cytoskeleton, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Neuronal Morphology, biology, Gene Expression Regulation, Developmental, Signaling cascades, Cellular Structures, Cell biology, Cytokines, Protein Binding, Research Article, MAPK signaling cascades, Dendritic Spines, Neurogenesis, CREB, Signaling Pathways, 03 medical and health sciences, Developmental Neuroscience, Animals, Biology, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Brain-derived neurotrophic factor, Binding Sites, Brain-Derived Neurotrophic Factor, Gene Expression Profiling, lcsh:R, Molecular Development, Molecular biology, Rats, Cellular Neuroscience, Synapses, biology.protein, Protein Translation, lcsh:Q, Neural Circuit Formation, Molecular Neuroscience, Carrier Proteins, rhoA GTP-Binding Protein, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology, Neuroscience, Synaptic Plasticity |
| الوصف: | Neurotrophin-regulated gene expression is believed to play a key role in long-term changes in synaptic structure and the formation of dendritic spines. Brain-derived neurotrophic factor (BDNF) has been shown to induce increases in dendritic spine formation, and this process is thought to function in part by stimulating CREB-dependent transcriptional changes. To identify CREB-regulated genes linked to BDNF-induced synaptogenesis, we profiled transcriptional occupancy of CREB in hippocampal neurons. Interestingly, de novo motif analysis of hippocampal ChIP-Seq data identified a non-canonical CRE motif (TGGCG) that was enriched at CREB target regions and conferred CREB-responsiveness. Because cytoskeletal remodeling is an essential element of the formation of dendritic spines, within our screens we focused our attention on genes previously identified as inhibitors of RhoA GTPase. Bioinformatic analyses identified dozens of candidate CREB target genes known to regulate synaptic architecture and function. We showed that two of these, the RhoA inhibitors Par6C (Pard6A) and Rnd3 (RhoE), are BDNF-induced CREB-regulated genes. Interestingly, CREB occupied a cluster of non-canonical CRE motifs in the Rnd3 promoter region. Lastly, we show that BDNF-stimulated synaptogenesis requires the expression of Par6C and Rnd3, and that overexpression of either protein is sufficient to increase synaptogenesis. Thus, we propose that BDNF can regulate formation of functional synapses by increasing the expression of the RhoA inhibitors, Par6C and Rnd3. This study shows that genome-wide analyses of CREB target genes can facilitate the discovery of new regulators of synaptogenesis. |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25400c970061706a07b60a5a5466fc65 https://doi.org/10.1371/journal.pone.0064658 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....25400c970061706a07b60a5a5466fc65 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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