PMID- 23762244 OWN - NLM STAT- MEDLINE DCOM- 20140114 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 6 DP - 2013 TI - A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis. PG - e64658 LID - 10.1371/journal.pone.0064658 [doi] LID - e64658 AB - 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. FAU - Lesiak, Adam AU - Lesiak A AD - Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Program in Neuroscience, Washington State University, Pullman, Washington, United States of America. FAU - Pelz, Carl AU - Pelz C FAU - Ando, Hideaki AU - Ando H FAU - Zhu, Mingyan AU - Zhu M FAU - Davare, Monika AU - Davare M FAU - Lambert, Talley J AU - Lambert TJ FAU - Hansen, Katelin F AU - Hansen KF FAU - Obrietan, Karl AU - Obrietan K FAU - Appleyard, Suzanne M AU - Appleyard SM FAU - Impey, Soren AU - Impey S FAU - Wayman, Gary A AU - Wayman GA LA - eng GR - R01 MH086032/MH/NIMH NIH HHS/United States GR - MH086032/MH/NIMH NIH HHS/United States GR - NS066345/NS/NINDS NIH HHS/United States GR - R01 NS066345/NS/NINDS NIH HHS/United States GR - R01 DK083452/DK/NIDDK NIH HHS/United States GR - RDK083452/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20130606 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carrier Proteins) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Pard6a protein, rat) RN - 0 (Protein Isoforms) RN - EC 3.6.5.2 (RND3 protein, rat) RN - EC 3.6.5.2 (rho GTP-Binding Proteins) RN - EC 3.6.5.2 (rhoA GTP-Binding Protein) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Binding Sites MH - Brain-Derived Neurotrophic Factor/*genetics/metabolism MH - Carrier Proteins/*genetics/metabolism MH - Cells, Cultured MH - Cyclic AMP Response Element-Binding Protein/*genetics/metabolism MH - Dendritic Spines/*genetics/metabolism MH - Gene Expression Profiling MH - Gene Expression Regulation, Developmental MH - Genome-Wide Association Study MH - Hippocampus/cytology/growth & development/*metabolism MH - Neurogenesis/genetics MH - Promoter Regions, Genetic MH - Protein Binding MH - Protein Isoforms/genetics/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction MH - Synapses/*genetics/metabolism MH - rho GTP-Binding Proteins/*genetics/metabolism MH - rhoA GTP-Binding Protein/genetics/metabolism PMC - PMC3675129 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2013/06/14 06:00 MHDA- 2014/01/15 06:00 PMCR- 2013/06/06 CRDT- 2013/06/14 06:00 PHST- 2013/01/18 00:00 [received] PHST- 2013/04/16 00:00 [accepted] PHST- 2013/06/14 06:00 [entrez] PHST- 2013/06/14 06:00 [pubmed] PHST- 2014/01/15 06:00 [medline] PHST- 2013/06/06 00:00 [pmc-release] AID - PONE-D-13-03373 [pii] AID - 10.1371/journal.pone.0064658 [doi] PST - epublish SO - PLoS One. 2013 Jun 6;8(6):e64658. doi: 10.1371/journal.pone.0064658. Print 2013.