A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis

Adam Lesiak; Carl Pelz; Hideaki Ando; Mingyan Zhu; Monika Davare; Talley J Lambert; Katelin F Hansen; Karl Obrietan; Suzanne M Appleyard; Soren Impey; Gary A Wayman

doi:10.1371/journal.pone.0064658

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A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis

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A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis

Adam Lesiak, Carl Pelz, Hideaki Ando, Mingyan Zhu, Monika Davare, Talley J Lambert, Katelin F Hansen, Karl Obrietan, Suzanne M Appleyard, Soren Impey, …

PloS one, Vol.8(6), pp.e64658-e64658

2013

DOI: https://doi.org/10.1371/journal.pone.0064658

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https://hdl.handle.net/2376/111528

PMCID: PMC3675129

PMID: 23762244

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Abstract

Brain-Derived Neurotrophic Factor - genetics

rhoA GTP-Binding Protein - metabolism

Dendritic Spines - metabolism

Gene Expression Profiling

Synapses - genetics

rhoA GTP-Binding Protein - genetics

Neurogenesis - genetics

Protein Isoforms - metabolism

Synapses - metabolism

Gene Expression Regulation, Developmental

Brain-Derived Neurotrophic Factor - metabolism

Binding Sites

Hippocampus - growth & development

Promoter Regions, Genetic

Genome-Wide Association Study

rho GTP-Binding Proteins - genetics

Cells, Cultured

Rats

Hippocampus - cytology

Rats, Sprague-Dawley

Carrier Proteins - genetics

Cyclic AMP Response Element-Binding Protein - genetics

Hippocampus - metabolism

Adaptor Proteins, Signal Transducing

Carrier Proteins - metabolism

rho GTP-Binding Proteins - metabolism

Cyclic AMP Response Element-Binding Protein - metabolism

Protein Binding

Dendritic Spines - genetics

Protein Isoforms - genetics

Signal Transduction

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.

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Title: A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis
Creators: Adam Lesiak - Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Program in Neuroscience, Washington State University, Pullman, Washington, United States of America
Carl Pelz
Hideaki Ando
Mingyan Zhu
Monika Davare
Talley J Lambert
Katelin F Hansen
Karl Obrietan
Suzanne M Appleyard
Soren Impey
Gary A Wayman
Publication Details: PloS one, Vol.8(6), pp.e64658-e64658
Academic Unit: Department of Integrative Physiology and Neuroscience
Publisher: United States
Grant note: MH086032 / NIMH NIH HHS R01 MH086032 / NIMH NIH HHS NS066345 / NINDS NIH HHS R01 DK083452 / NIDDK NIH HHS RDK083452 / PHS HHS R01 NS066345 / NINDS NIH HHS
Identifiers: 99900547552401842
Language: English
Resource Type: Journal article