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Region‐specific regulation of 5‐HT1A receptor expression by Pet‐1‐dependent mechanisms in vivo
Author(s) -
Jacobsen Kirsten X.,
Czesak Margaret,
Deria Mariam,
Le François Brice,
Albert Paul R.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.07161.x
Subject(s) - tph2 , serotonergic , 5 ht1a receptor , raphe nuclei , biology , receptor , raphe , medicine , tryptophan hydroxylase , endocrinology , serotonin , 5 ht receptor , dorsal raphe nucleus , biochemistry
J. Neurochem. (2011) 116 , 1066–1076. 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.