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.