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

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere64658
JournalPLoS One
Volume8
Issue number6
DOIs
StatePublished - Jun 6 2013

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neurotrophins
Brain-Derived Neurotrophic Factor
Genes
Dendritic Spines
Genome
brain
genome
genes
GTP Phosphohydrolases
Nerve Growth Factors
Computational Biology
Genetic Promoter Regions
Synapses
guanosinetriphosphatase
synapse
Bioinformatics
bioinformatics
Gene expression
Neurons
synaptogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A Genome-Wide Screen of CREB Occupancy Identifies the RhoA Inhibitors Par6C and Rnd3 as Regulators of BDNF-Induced Synaptogenesis. / Lesiak, Adam; Pelz, Carl; Ando, Hideaki; Zhu, Mingyan; Davare, Monika; Lambert, Talley J.; Hansen, Katelin F.; Obrietan, Karl; Appleyard, Suzanne M.; Impey, Soren; Wayman, Gary A.

In: PLoS One, Vol. 8, No. 6, e64658, 06.06.2013.

Research output: Contribution to journalArticle

Lesiak, A, Pelz, C, Ando, H, Zhu, M, Davare, M, Lambert, TJ, Hansen, KF, Obrietan, K, Appleyard, SM, Impey, S & Wayman, GA 2013, 'A Genome-Wide Screen of CREB Occupancy Identifies the RhoA Inhibitors Par6C and Rnd3 as Regulators of BDNF-Induced Synaptogenesis', PLoS One, vol. 8, no. 6, e64658. https://doi.org/10.1371/journal.pone.0064658
Lesiak, Adam ; Pelz, Carl ; Ando, Hideaki ; Zhu, Mingyan ; Davare, Monika ; Lambert, Talley J. ; Hansen, Katelin F. ; Obrietan, Karl ; Appleyard, Suzanne M. ; Impey, Soren ; Wayman, Gary A. / A Genome-Wide Screen of CREB Occupancy Identifies the RhoA Inhibitors Par6C and Rnd3 as Regulators of BDNF-Induced Synaptogenesis. In: PLoS One. 2013 ; Vol. 8, No. 6.
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AU - Lambert, Talley J.

AU - Hansen, Katelin F.

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