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The Journal of Neuroscience, February 8, 2006, 26(6):1864-1871; doi:10.1523/JNEUROSCI.2643-05.2006
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Neurobiology of Disease
Cell-Specific Repressor or Enhancer Activities of Deaf-1 at a Serotonin 1A Receptor Gene Polymorphism
Margaret Czesak, * Sylvie Lemonde, * Erica A. Peterson, Anastasia Rogaeva, andPaul R. Albert Ottawa Health Research Institute (Neuroscience), Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada K1H 8M5
Correspondence should be addressed to Paul R. Albert at the above address. Email: palbert{at}uottawa.ca
The serotonin-1A (5-HT1A) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT1A receptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT1A promoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR)/Deaf-1 and Hes5, at the 5-HT1A C(-1019) site. In serotonergic raphe RN46A cells, Deaf-1 and Hes5 repressed the 5-HT1A receptor gene at the C(-1019)-allele but not the G(-1019)-allele. However, in nonserotonergic cells that express 5-HT1A receptors (septal SN48, neuroblastoma SKN-SH, and neuroblastoma/glioma NG108–15 cells), Deaf-1 enhanced 5-HT1A promoter activity at the C(-1019)-allele but not the G-allele, whereas Hes5 repressed in all cell types. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression. To test whether Deaf-1 activity is intrinsic, the activity of a Gal4DBD (DNA binding domain)-Deaf-1 fusion protein at a heterologous Gal4 DNA element was examined. Gal4DBD-Deaf-1 repressed transcription in RN46A cells but enhanced transcription in SN48 cells, indicating that these opposite activities are intrinsic to Deaf-1. Repressor or enhancer activities of Deaf-1 or Gal4DBD-Deaf-1 were blocked by histone deacetylase inhibitor trichostatin A. Thus, the intrinsic activity of Deaf-1 at the 5-HT1A promoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders.
Key words: 5-HT1A receptor; transcription factor; epigenetic; raphe; polymorphism; anxiety; major depressive disorder
Received June 27, 2005; revised Dec. 20, 2005; accepted Dec. 22, 2005.
Correspondence should be addressed to Paul R. Albert at the above address. Email: palbert{at}uottawa.ca
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