Leukemia Inhibitory Factor and Embryo Development

胚胎植入是哺乳动物生殖的关键步骤。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。子宫通过蜕膜化对入侵的胚胎作出反应，其作用是限制胚胎入侵并培育植入的胚胎。在预期着床时，子宫在卵巢类固醇激素、雌激素和孕酮的控制下经历一系列增殖和分化变化，这些激素或直接作用于细胞，或通过诱导局部产生的生长因子和细胞因子。其中白血病抑制因子（LIF），我们首先显示抑制小鼠胚胎干细胞（ES）的分化。在小鼠和其他哺乳动物中，包括人类，LIF在植入时在子宫中强烈表达，并且在小鼠中，这是在雌激素的控制下。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如何影响子宫容受性，激活哪些信号转导途径以及这些途径如何受类固醇激素的调节。我们还对鉴定子宫中受LIF控制的基因感兴趣，并且正在开发组织特异性方法，通过这些方法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症的一些主要原因。他们也可以提供见解上皮基质的相互作用是如何介导的类固醇激素和生长因子。后者应该有助于理解许多癌症是如何以及为什么从体内的上皮细胞群中产生的。

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 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.