A genomic approach to identify novel progesterone receptor regulated pathways in the uterus during implantation
A genomic approach to identify novel progesterone receptor regulated pathways in the uterus during implantation
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DOI：
10.1210/me.2002-0270
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发表时间：
2002-12-01
影响因子：
--
通讯作者：
Bagchi, MK
中科院分区：
文献类型：
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作者：
Cheon, YP;Li, QX;Bagchi, MK
类固醇激素孕酮（P）的细胞作用通过其核受体介导，所述核受体调节特定靶基因的表达。然而，在生殖周期和妊娠的各个阶段，子宫中由P受体（PR）调节的基因网络的身份在很大程度上仍然未知。在这项研究中，我们已经使用寡核苷酸微阵列来确定mRNA的表达在怀孕的小鼠子宫调节RU486，一个良好的特点PR拮抗剂，这也是一个有效的抑制剂植入。我们发现，作为对RU486的响应，在着床前小鼠子宫中，对应于78个已知基因的mRNA表达下调至少2倍。这些基因中的几个的PR调节通过将P施用到卵巢切除的野生型和PR敲除（PRKO）小鼠来确定。对这些基因在妊娠子宫中的详细时空分析表明，它们在上皮和间质中的表达可能与PR在这些细胞类型中的表达相关。此外，时间进程研究表明，这些基因中的许多可能是PR调节的主要靶点。我们还鉴定了70个已知的基因，这些基因在妊娠子宫中响应RU486上调至少2倍。有趣的是，一些RU486诱导基因的初步研究表明，它们的子宫表达也受到雌激素的调节。在生殖道中鉴定几个Hovel PR调节的基因通路是理解P如何调节导致着床的生理事件的重要一步。
The cellular actions of steroid hormone progesterone (P) are mediated via its nuclear receptors, which regulate the expression of specific target genes. The identity of gene networks that are regulated by the P receptors (PRs) in the uterus at various stages of the reproductive cycle and pregnancy, however, remain largely unknown. In this study, we have used oligonucleotide microarrays to identify mRNAs whose expression in the pregnant mouse uterus is modulated by RU486, a well-characterized PR antagonist, which is also an effective inhibitor of implantation. We found that, in response to RU486, expression of mRNAs corresponding to 78 known genes was down-regulated at least 2-fold in the preimplantation mouse uterus. The PR regulation of several of these genes was ascertained by administering P to ovariectomized wild-type and PR knockout (PRKO) mice. Detailed spatio-temporal analysis of these genes in the pregnant uterus indicated that their expression in the epithelium and stroma could be correlated with the expression of PR in those cell types. Furthermore, time-course studies suggested that many of these genes are likely primary targets of PR regulation. We also identified 70 known genes that were up-regulated at least 2-fold in the pregnant uterus in response to RU486. Interestingly, initial examination of a number of RU486-inducible genes reveals that their uterine expression is also regulated by estrogen. The identification of several hovel PR-regulated gene pathways in the reproductive tract is an important step toward understanding how P regulates the physiological events leading to implantation.