Deng Wen-Bo, Liang Xiao-Huan, Liu Ji-Long, Yang Zeng-Ming
College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Endocrinology. 2014 Jul;155(7):2704-17. doi: 10.1210/en.2014-1015. Epub 2014 May 5.
Thyroid dysfunction during human pregnancy is closely related to serious pregnancy outcome. However, the regulation and function of thyroid hormones during early pregnancy are largely unknown. We found that type II deiodinase, an enzyme converting T4 to activated T3, is highly expressed in the mouse uterus on days 3 and 4 of pregnancy. Once the embryo implants into the receptive uterus, type III deiodinase (Dio3), a mainly paternally imprinted gene for inactivating T3, is significantly induced in the stromal cells and accompanied by DNA hypermethylation of intergenic differentially CpG methylation regions in the δ-like 1 homolog-Dio3 imprinting cluster. The concentration of uterine free T3 is actually decreased after embryo implantation. T3 induces Dio3 expression both in vivo and in vitro, suggesting a positive feedback loop. T3 addition or Dio3 knockdown compromises decidualization. These results indicate that the Dio3-mediated local T3 decrease is critical for decidualization of stromal cells during early pregnancy. Furthermore, we found that progesterone regulates Dio3 expression through its cognate receptor both in vivo and in vitro. Additionally, cAMP regulates Dio3 transcription through the protein kinase A-cAMP response element-binding protein pathway. The inhibition of the protein kinase A pathway results in decreased Dio3 expression and impaired decidualization. Dio3 opposite strand (Dio3os) expressed in a similar pattern to Dio3, is transcribed from the opposite strand of Dio3 and fine-tunes Dio3 expression during decidualization. Our data indicate that Dio3 is strongly expressed and tightly controlled during decidualization.
人类孕期甲状腺功能障碍与严重的妊娠结局密切相关。然而，妊娠早期甲状腺激素的调节和功能在很大程度上尚不清楚。我们发现，II型脱碘酶，一种将T4转化为活性T3的酶，在妊娠第3天和第4天的小鼠子宫中高表达。一旦胚胎植入接受性子宫，III型脱碘酶（Dio3），一种主要由父系印记的使T3失活的基因，在基质细胞中被显著诱导，并伴随着δ样1同源物-Dio3印记簇中基因间差异CpG甲基化区域的DNA高甲基化。胚胎植入后子宫游离T3的浓度实际上会降低。T3在体内和体外均诱导Dio3表达，提示存在正反馈回路。添加T3或敲低Dio3会损害蜕膜化。这些结果表明，Dio3介导的局部T3降低对妊娠早期基质细胞的蜕膜化至关重要。此外，我们发现孕酮在体内和体外均通过其同源受体调节Dio3表达。此外，cAMP通过蛋白激酶A- cAMP反应元件结合蛋白途径调节Dio3转录。抑制蛋白激酶A途径会导致Dio3表达降低和蜕膜化受损。以与Dio3相似的模式表达的Dio3反义链（Dio3os）从Dio3的反义链转录而来，并在蜕膜化过程中微调Dio3表达。我们的数据表明，Dio3在蜕膜化过程中强烈表达且受到严格控制。
