Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling

Abstract

Doherty LF, Kwon HE, Taylor HS. Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling. Am J Physiol Endocrinol Metab 300: E86-E93, 2011. First published October 19, 2010 doi:10.1152/ajpendo.00439.2010.-Tryptophan 2,3-dioxygenase (TDO) is expressed in endometrium and catabolizes tryptophan, a precursor in the biosynthesis of serotonin. Tryptophan metabolism is an important mechanism for regulation of serotonin levels. Preimplantation mouse embryos are known to express serotonin receptors, specifically the 5-HT1D and 5-HT7 serotonin receptor subtypes. Here we demonstrate that Hoxa10 regulates endometrial TDO expression and improves embryo viability through increased serotonin production. Transfection of pcDNA-Hoxa10 to the murine uterus increased total TDO expression. In vitro, epithelial cell TDO expression was decreased after transfection with Hoxa10. Decreased glandular TDO in response to HOXA10 may augment serotonin production by increasing tryptophan availability. Conversely, stromal TDO expression increased with constitutive Hoxa10 expression. In mice, epithelial serotonin was increased in response to constitutive expression of Hoxa10. Embryo quality was impaired after treatment with Hoxa10 antisense. Blockade of serotonin receptors 1D and 7 also resulted in impaired embryo development, indicating an essential role for Hoxa10 induction of TDO and subsequent serotonin production in embryo development. Transfection of pcDNA-TDO also decreased the number of T cells in the endometrial stroma. We have shown a novel mechanism by which HOXA10 regulates endometrial TDO expression. In the endometrial stroma, HOXA10 increases TDO mRNA, which may increase tryptophan catabolism, allowing for immune tolerance at the time of embryo implantation. In endometrial glands, HOXA10 decreases TDO mRNA leading to increased serotonin that in turn acts to promote normal embryo development. tryptophan degradation; implantation; serotonin THE INDUCTION OF RECEPTIVITY in the mammalian endometrium requires specific molecular and structural alterations in response to hormonal signals. These changes occur within the glandular epithelium and the endometrial stroma to create a favorable environment for embryo implantation. The specific genes responsible for inducing endometrial receptivity, as well as their regulation and function at the time of implantation, remain incompletely characterized.Hoxa10 is a member of the homeobox (Hox) gene family, which encodes transcription factors that function to control embryonic development and to regulate gene expression within the endometrium during the menstrual cycle (39). Hox genes expressed within the reproductive tract regulate normal developmental patterning during the embryonic period and continue to function in the adult. Hoxa10 is expressed by the endometrial glands and stroma throughout the menstrual cycle and its expression is regulated by estradiol and progesterone (36, 38). Mice with targeted disruption of either Hoxa10 or Hoxa11 are infe...

Leiomyoma-derived transforming growth factor-β impairs bone morphogenetic protein-2-mediated endometrial receptivity

“…The targeted disruption of these genes in mice results in infertility due to failed endometrial receptivity (4–7). HOX genes regulate a number of molecules that function during the window of implantation including: pinopodes, β3 Integrin, Tryptophan dioxygenase, and insulin-like-growth-factor-binding-protein-I (IGFBP-I) (8–11). There are no known human mutations of the HOXA10 or HOXA11 genes; however women affected by conditions known to be associated with implantation defects, including submucosal myomas, have diminished expression of these genes (12–15).…”

Differential expression and regulation of Tdo2 during mouse decidualization

“…Tryptophan is an essential amino acid that is required for the biosynthesis of proteins and also a precursor of neurotransmitter 5-hydroxytryptamine (serotonin) which has been identified within the CNS, vasculature, gastrointestinal tract, and female reproductive tract (Stone & Darlington 2002, Doherty et al 2011. In mammals, most of tryptophan was metabolized along the kynurenine pathway and tryptophan metabolism was closely correlated with pregnancy (Stone & Darlington 2002, Schröcksnadel et al 2006.…”

“…Tdo2 has also been identified in skin, brain, epididymis, testis, and early concepti, although it was mainly expressed in the liver (Suzuki et al 2001, Minatogawa et al 2003, Britan et al 2006. Accumulating data have shown that Tdo2 was expressed in endometrial stromal cells and could be regulated by Hoxa10 gene, which was essential for decidualization (Benson et al 1996, Germeyer et al 2009, Doherty et al 2011, Zhang et al 2013. According to our (B Guo and X-C Tian unpublished observations) microarray data, Tdo2 was strongly expressed by day 8 decidua and deciduoma under artificial decidualization compared with the untreated uterine horn.…”

Polymorphic variants of the serotonin receptor, 5-HT1A, and the serotonin transporter, 5-HTTLPR, and adverse pregnancy outcomes: A pilot study

“…31 Moreover, they were able to localize the phenomenon in the endometrial glands receptivity, showing a positive correlation between modulation of serotonin levels via HOXA 10 transcription factor and pregnancy establishment; increased levels of serotonin in the maternal endometrium were associated with normal pregnancy establishment and progression. 32 Taken together, these studies show the association between the SERT and 5-HTA1 and pregnancy establishment, especially the role of decreased activity of the 5-HTA1 receptor in the presence of the CC genotype. The current study adds a novel tier/stratum suggestive of an alternative explanation for the pathology of EPL.…”