Leukemia Inhibitory Factor and Embryo Development

胚胎着床是哺乳动物生殖过程中的关键步骤。在这一点上，胚胎与母体子宫组织形成更密切的联系。在许多哺乳动物中，这涉及胚胎与子宫的物理附着，随后胚胎滋养层侵入母体组织。子宫通过蜕皮化对侵入的胚胎作出反应，既限制胚胎侵入，又滋养着植入的胚胎。 在植入的预期中，子宫在卵巢类固醇激素、雌激素和孕酮的控制下经历了一系列的增殖和分化变化，这些激素要么直接作用于细胞，要么通过诱导局部产生的生长因子和细胞因子来作用。后者是我们首次发现的抑制小鼠胚胎干细胞分化的白血病抑制因子(LIF)。在小鼠和包括人类在内的其他哺乳动物中，LIF在着床时在子宫中强烈表达，而在小鼠中，这是受雌激素控制的。LIF对于胚胎植入是必不可少的，因为缺乏功能性LIF基因的雌性小鼠是不育的，囊胚无法植入。 我们目前正在研究LIF如何影响子宫的接受性，哪些信号转导通路被激活，以及这些信号转导通路是如何被类固醇激素调节的。我们还对识别子宫中受LIF控制的基因感兴趣，并正在开发组织特异性手段，通过这些手段我们可以操纵它们的表达，以确定它们的功能。这些研究应该有助于了解不孕不育的一些主要原因。它们还可能提供关于类固醇激素和生长因子如何介导上皮-间质相互作用的见解。后者应该有助于理解许多癌症是如何以及为什么产生于体内的上皮细胞群体。

Embryo implantation is a critical step in mammalian reproduction. At this point the embryo forms a more intimate connection with the maternal uterine tissues. In many mammals this involves physical attachment of the embryo to the uterus with subsequent invasion of the maternal tissues by the embryonic trophoblast. The uterus responds to the invading embryo by decidualizing which acts to both restrict embryo invasion and to nurture the implanted embryo. In anticipation of implantation the uterus undergoes a series of proliferative and differentiative changes under control of the ovarian steroid hormones, estrogen and progesterone that act either directly on cells or via the induction of locally produced growth factors and cytokines. Among the latter is Leukemia Inhibitory Factor (LIF) that we first showed inhibited the differentiation of mouse embryonic stem (ES) cells. In mice and other mammals, including humans, LIF is strongly expressed in the uterus at the time of implantation and that in mice this is under the control of estrogen. LIF is essential for embryo implantation, as female mice lacking a functional LIF gene are sterile with the blastocysts failing to implant. We are currently investigating how LIF affects uterine receptivity, what signal transduction pathways are activated and how these are regulated by the steroid hormones. We are also interested in identifying genes that are controlled by LIF in the uterus and are developing tissues specific means by which we can manipulate their expression to determine their function. These studies should help understand some of the major causes of infertility. They may also provide insights as to how epithelial-stromal interactions are mediated by steroid hormones and growth factors. The latter should help understand how and why many cancers arise from epithelial cell populations in the body.