LEUKEMIA INHIBITORY FACTOR AND EMBRYO DEVELOPMENT

胚胎植入是哺乳动物繁殖的关键步骤。此时，胚胎与母体子宫组织形成更紧密的联系。在许多哺乳动物中，这包括胚胎与子宫的物理附着，随后胚胎滋养细胞侵入母体组织。子宫对入侵胚胎的反应是脱卵，这既限制了胚胎的入侵，又滋养了植入的胚胎。在植入前，子宫在卵巢类固醇激素、雌激素和黄体酮的控制下发生一系列增殖和分化变化，这些激素直接作用于细胞或通过诱导局部产生的生长因子和细胞因子。后者是白血病抑制因子（LIF），我们首次发现它能抑制胚胎干细胞（ES）的分化。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，这是在雌激素的控制下表达的。LIF对于胚胎着床至关重要，因为缺乏功能性LIF基因的雌性小鼠由于囊胚不能着床而不育。我们目前正在研究LIF如何影响子宫接受性，哪些信号转导途径被激活，以及这些信号转导途径如何受到类固醇激素的调节。我们也有兴趣确定哪些基因是由子宫内的LIF控制的，并且正在发育特定的组织，通过这种方式我们可以操纵它们的表达来确定它们的功能。这些研究应该有助于了解不孕不育的一些主要原因。它们也可能提供关于上皮-基质相互作用是如何由类固醇激素和生长因子介导的见解。后者应该有助于理解许多癌症是如何以及为什么由体内上皮细胞群产生的。

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 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 determining which genes 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.