Background
Altered expression of serotonin-1A (5-HT1A) receptors, both presynaptic in the raphe
nuclei and post-synaptic in limbic and cortical target areas, has been implicated
in mood disorders such as major depression and anxiety. Within the 5-HT1A receptor
gene, a powerful dual repressor element (DRE) is regulated by two protein complexes:
Freud-1/CC2D1A and a second, unknown repressor. Here we identify human Freud-2/CC2D1B,
a Freud-1 homologue, as the second repressor.
Methods
Freud-2 distribution was examined with Northern and Western blot, reverse transcriptase
polymerase chain reaction, and immunohistochemistry/immunofluorescence; Freud-2 function
was examined by electrophoretic mobility shift, reporter assay, and Western blot.
Results
Freud-2 RNA was widely distributed in brain and peripheral tissues. Freud-2 protein
was enriched in the nuclear fraction of human prefrontal cortex and hippocampus but
was weakly expressed in the dorsal raphe nucleus. Freud-2 immunostaining was co-localized
with 5-HT1A receptors, neuronal and glial markers. In prefrontal cortex, Freud-2 was
expressed at similar levels in control and depressed male subjects. Recombinant hFreud-2
protein bound specifically to 5′ or 3′ human DRE adjacent to the Freud-1 site. Human
Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter
in human HEK-293 5-HT1A-negative cells and neuronal SK-N–SH cells, a model of postsynaptic
5-HT1A receptor-positive cells. Furthermore, small interfering RNA knockdown of endogenous
hFreud-2 expression de-repressed 5-HT1A promoter activity and increased levels of
5-HT1A receptor protein in SK-N–SH cells.
Conclusions
Human Freud-2 binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene
to regulate its expression in non-serotonergic cells and neurons.
Key Words
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Article info
Publication history
Published online: May 08, 2009
Accepted:
February 28,
2009
Received in revised form:
February 11,
2009
Received:
August 20,
2008
Identification
Copyright
© 2009 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
