Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling.
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.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Leo F
LF
Doherty
Hye Eun
HE
Kwon
Hugh S
HS
Taylor
D000818:Animals; D002460:Cell Line; D016373:DNA, Antisense / Q000235:genetics / Q000378:metabolism; D010064:Embryo Implantation / Q000276:immunology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047108:Embryonic Development / Q000187:drug effects; D004717:Endometrium / Q000276:immunology / Q000378:metabolism; D005260:Female; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D044346:Receptor, Serotonin, 5-HT1D / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000166:cytology / Q000378:metabolism
D016373:DNA, Antisense; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; C069634:HOXA10 protein, human; C092119:Hoxa10 protein, mouse; D014366:Tryptophan Oxygenase