Role of Hoxa-10 and Hoxa-11 in Mouse Implantation

哺乳动物着床是早期胚胎发育的重要步骤，涉及内分泌、旁分泌和细胞事件的同步，使早期胚胎具有子宫接受性。然而，关于植入囊胚和激素启动子宫之间的分子相互作用知之甚少。两个母系表达的abalb样同源盒基因Hoxa-10和Hoxa-11与植入子宫的准备和功能有关。缺乏Hoxa-10的小鼠表现出由于子宫基质缺陷而使子宫接受性降低的雌性生育能力。在分子上，Hoxa-10在激素调控的途径中发挥作用，并可能与另一个涉及前列腺素E2及其受体的植入途径汇合。此外，Hoxa-10及其邻近基因Hoxa-11已被证明是激素介导的基质细胞在植入过程中增殖所必需的。总的来说，这些结果将Hoxa-10和Hoxa-11置于激素调控的植入途径的顶端，并表明这两个基因可能负责许多激素诱导的生理变化。该基金拟对当前模型进行测试，首先在位点特异性敲除小鼠中证明，孕激素通过两种推测的孕激素反应元件在植入过程中直接调节Hoxa-10和Hoxa-11基因在体内的表达。其次，马博士将寻找这两种转录因子控制的候选靶基因，特别关注在着床子宫中介导激素诱导细胞增殖的细胞周期调节因子。这些实验的结果将大大有助于理解植入过程，并将开始建立控制哺乳动物植入的遗传途径。

0131316MaMammalian implantation is an essential step during early embryonic development and involves the synchronization of endocrine, paracrine, and cellular events which confers uterine receptivity to the early embryo. However, very little is known about the molecular interactions between implanting blastocysts and the hormonally primed uterus. Two maternally expressed AbdominalB-like homeobox genes, Hoxa-10 and Hoxa-11, have been implicated in the preparation and functioning of the implanting uterus. Mice deficient for Hoxa-10 exhibit reduced female fertility due to defects in the uterine stroma to confer uterine receptivity. Molecularly, Hoxa-10 functions in a hormonally regulated pathway and likely converges with another implantation pathway involving prostaglandin E2 and its receptors. In addition, both Hoxa-10 and its neighboring gene Hoxa-11 have been shown to be required for hormone-mediated stromal cell proliferation during implantation. Collectively, these results place Hoxa-10 and Hoxa-11 at the top of a hormone-regulated implantation pathway and suggest that these two genes may be responsible for many hormone-induced physiological changes.This grant proposes to test the current model, first by demonstrating in site-specific knockout mice that progesterone directly regulate Hoxa-10 and Hoxa-11 gene expression in vivo during implantation through the two putative progesterone response elements. Second, Dr. Ma will search for candidate target genes controlled by these two transcription factors, with special focus on cell cycle regulatory factors which could mediate hormone-induced cellular proliferation in the implantation uterus. Results from these experiments should contribute substantially to the understanding of the implantation process and will start the process of building a genetic pathway controlling mammalian implantation.