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Keywords:

  • major depressive disorder;
  • receptor;
  • repression;
  • serotonin;
  • serotonin-1A

Abstract

The CC2D1A/Freud-1 gene has recently been linked to non-syndromic mental retardation and a short isoform of mouse Five prime REpressor Under Dual repression binding protein 1 (Freud-1) can repress the serotonin-1A (5-HT1A) receptor gene in rodent cells. In this study, we addressed the expression, localization and regulation of the human 5-HT1A receptor gene by a long isoform of human Freud-1 protein (Freud-1L). We show that human CC2D1A/Freud-1 RNA is expressed in brain and peripheral tissues and encodes short and long isoforms, which differ by an upstream in-frame translational start site. Whereas previous studies identified the short isoform of Freud-1 as the predominant isoform in rodent cells, we demonstrate that the long isoform is more abundant in human cells, especially in the nuclear fraction. The nuclear localization of Freud-1L was enriched upon inhibition of chromosome region maintenance 1/exportin 1-dependent nuclear export, indicating a dynamic regulation of Freud-1 nuclear localization. Consistent with a functional role in the nucleus, human Freud-1L bound specifically to its dual repressor element in the 5-HT1A receptor gene in vitro and repressed transcription from these sites. Importantly, chromatin immunoprecipitation using antibodies specific for human Freud-1L demonstrated that it is bound to the dual repressor element in chromatin, indicating a functional role in regulating the basal expression of the 5-HT1A receptor gene. Taken together, these results indicate that both the short and long isoforms of Freud-1 are expressed, although Freud-1L is the major isoform that regulates the human 5-HT1A receptor gene. Disruption of transcriptional regulation by mutation of Freud-1 may play a role in abnormal brain function leading to mental retardation.