Region-specific regulation of 5-HT1A receptor expression by Pet-1-dependent mechanisms in vivo.

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is negatively regulated by 5-HT1A autoreceptors on raphe neurons, and is implicated in mood disorders. Pet-1/FEV is an ETS transcription factor expressed exclusively in serotonergic neurons and is essential for serotonergic differentiation, although its regulation of 5-HT receptors has not yet been studied. Here, we show by electrophoretic mobility shift assay that recombinant human Pet-1/FEV binds directly to multiple Pet-1 elements of the human 5-HT1A receptor promoter to enhance its transcriptional activity. In luciferase reporter assays, mutational analysis indicated that while several sites contribute, the Pet-1 site at -1406 bp had the greatest effect on 5-HT1A promoter activity. To address the effect of Pet-1 on 5-HT1A receptor regulation in vivo, we compared the expression of 5-HT1A receptor RNA and protein in Pet-1 null and wild-type littermate mice. In the raphe nuclei of Pet-1-/- mice tryptophan hydroxylase 2 (TPH2) RNA, and 5-HT and TPH immunostaining were greatly reduced, indicating a deficit in 5-HT production. Raphe 5-HT1A RNA and protein levels were also reduced in Pet-1-deficient mice, consistent with an absence of Pet-1-mediated transcriptional enhancement of 5-HT1A autoreceptors in serotonergic neurons. Interestingly, 5-HT1A receptor expression was up-regulated in the hippocampus, but down-regulated in the striatum and cortex. These data indicate that, in addition to transcriptional regulation by Pet-1 in raphe neurons, 5-HT1A receptor expression is regulated indirectly by alterations in 5-HT neurotransmission in a region-specific manner that together may contribute to the aggressive/anxiety phenotype observed in Pet-1 null mice.

• Authors: Kirsten X Jacobsen, Margaret Czesak, Mariam Deria, Brice Le François, Paul R Albert
• Journal: Journal of neurochemistry (J Neurochem) Vol. 116 Issue 6 Pg. 1066-76 (Mar 2011) ISSN: 1471-4159 [Electronic] England
• PMID: 21182526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Chemical References

• Fev protein, mouse
• RNA, Messenger
• Transcription Factors
• Receptor, Serotonin, 5-HT1A
• Tryptophan Hydroxylase

Topics

• Analysis of Variance
• Animals
• Brain (anatomy & histology, metabolism)
• Cell Line, Transformed
• Cell Line, Tumor
• Electrophoretic Mobility Shift Assay
• Gene Expression Regulation (genetics, physiology)
• Humans
• Mice
• Mice, Knockout
• Neuroblastoma
• Promoter Regions, Genetic (physiology)
• RNA, Messenger (metabolism)
• Rats
• Receptor, Serotonin, 5-HT1A (genetics, metabolism)
• Transcription Factors (deficiency, physiology)
• Transfection (methods)
• Tryptophan Hydroxylase (genetics, metabolism)