Mohamed Othman A, Dufort Daniel, Clarke Hugh J
Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada H3A 1A1.
Biol Reprod. 2004 Aug;71(2):417-24. doi: 10.1095/biolreprod.103.025692. Epub 2004 Mar 24.
Implantation of mammalian embryos depends on differentiation of the blastocyst to a competent state and of the uterine endometrium to a receptive state. Communication between the blastocyst and uterus ensures that these changes are temporally coordinated. Although considerable evidence indicates that the blastocyst induces expression of numerous genes in uterine tissue, potential signaling mechanisms have yet to be identified. Moreover, whereas a surge of maternal estradiol occurring on Day 4 of pregnancy in the mouse is critically required for many of the peri-implantation uterine changes, whether this surge also affects blastocyst gene expression has not been established. We show here that mouse morulae express genes encoding several members of the Wnt family of signaling molecules. Additional Wnt genes are newly expressed following development to blastocyst. Unexpectedly, Wnt5a and Wnt11 are expressed in embryos that undergo the morula-to-blastocyst transition in vivo, but only weakly or not at all in embryos that do so in vitro. Upregulation of Wnt11 is temporally coordinated with the surge of maternal estradiol on Day 4. Wnt11 fails to be upregulated in blastocysts obtained from mice ovariectomized early on Day 4 or from mice treated with the estradiol antagonist, ICI 182,780. Administration of estradiol-17beta or its metabolite, 4-OH-estradiol, to ovariectomized mice restores Wnt11 expression. Moreover, Wnt11 expression is not upregulated when blastocysts are trapped in the oviduct following ligation of the utero-tubal junction, nor when estradiol-17beta or 4-OH-estradiol are administered to blastocysts in vitro. These results establish a comprehensive profile of Wnt gene expression during late preimplantation development, demonstrate that estradiol regulates gene expression in the blastocyst via uterine factors, and identify Wnts as potential mediators of embryo-uterine communication during implantation.
哺乳动物胚胎的着床取决于囊胚分化为有能力的状态以及子宫内膜分化为接受状态。囊胚与子宫之间的通讯确保了这些变化在时间上的协调。尽管大量证据表明囊胚可诱导子宫组织中众多基因的表达，但潜在的信号传导机制尚未确定。此外，虽然小鼠怀孕第4天母体雌二醇的激增对于许多着床周围子宫变化至关重要，但这种激增是否也影响囊胚基因表达尚未明确。我们在此表明，小鼠桑葚胚表达编码信号分子Wnt家族几个成员的基因。发育至囊胚后，其他Wnt基因开始新表达。出乎意料的是，Wnt5a和Wnt11在体内经历桑葚胚到囊胚转变的胚胎中表达，但在体外进行这种转变的胚胎中表达微弱或根本不表达。Wntll的上调在时间上与第4天母体雌二醇的激增相协调。在第4天早期卵巢切除的小鼠或用雌二醇拮抗剂ICI 182,780处理的小鼠所获得的囊胚中，Wntll未能上调。给卵巢切除的小鼠施用雌二醇-17β或其代谢物4-羟基雌二醇可恢复Wntll的表达。此外，当子宫输卵管连接处结扎后囊胚被困在输卵管中时，或者当在体外将雌二醇-17β或4-羟基雌二醇施用于囊胚时，Wntll表达不上调。这些结果建立了着床前晚期发育过程中Wnt基因表达的全面概况，证明雌二醇通过子宫因子调节囊胚中的基因表达，并确定Wnts是着床期间胚胎与子宫通讯的潜在介质。
