Tulac S, Nayak N R, Kao L C, Van Waes M, Huang J, Lobo S, Germeyer A, Lessey B A, Taylor R N, Suchanek E, Giudice L C
Department of Gynecology and Obstetrics, Stanford University, Stanford, California 94305-5317, USA.
J Clin Endocrinol Metab. 2003 Aug;88(8):3860-6. doi: 10.1210/jc.2003-030494.
Members of the Wnt family of signaling molecules are important in cell specification and epithelial-mesenchymal interactions, and targeted gene deletion of Wnt-7a in mice results in complete absence of uterine glands and infertility. To assess potential roles of the Wnt family in human endometrium, an endocrine-responsive tissue, we investigated in the proliferative and secretory phases of the menstrual cycle, endometrial expression of several Wnt ligands (Wnt-2, Wnt-3, Wnt-4, Wnt-5a, Wnt-7a, and Wnt-8b), receptors [Frizzled (Fz)-6 and low-density lipoprotein receptor-related protein (LRP)-6], inhibitors [FrpHE and Dickkopf (Dkk)-1], and downstream effectors (Dishevelled-1, glycogen synthase kinase-3beta, and beta-catenin) by RT-PCR, real-time PCR and in situ hybridization. No significant menstrual cycle dependence of the Wnt ligands (except Wnt-3), receptors, or downstream effectors, was observed. Wnt-3 increased 4.7-fold in proliferative compared with secretory endometrium (P < 0.05). However, both inhibitors showed dramatic changes during the cycle, with 22.2-fold down-regulation (P < 0.05) of FrpHE and 234.3-fold up-regulation (P < 0.001) of Dkk-1 in the secretory, compared with the proliferative phase. In situ hybridization revealed cell-specific expression of different Wnt family genes in human endometrium. Wnt-7a was exclusively expressed in the luminal epithelium, and Fz-6 and beta-catenin were expressed in both epithelium and stroma, without any apparent change during the cycle. Both FrpHE and Dkk-1 expression were restricted to the stroma, during the proliferative and secretory phase, respectively. These unique expression patterns of Wnt family genes in different cell types of endometrium and the differential regulation of the inhibitors during the proliferative and secretory phase of the menstrual cycle strongly suggest functions for a Wnt signaling dialog between epithelial and stromal components in human endometrium. Also, they underscore the likely importance of this family during endometrial development, differentiation and implantation.
Wnt信号分子家族的成员在细胞特化和上皮-间质相互作用中发挥着重要作用，小鼠中Wnt-7a基因的靶向缺失会导致子宫腺体完全缺失和不孕。为了评估Wnt家族在人子宫内膜（一种内分泌反应性组织）中的潜在作用，我们在月经周期的增殖期和分泌期，通过逆转录聚合酶链反应（RT-PCR）、实时定量聚合酶链反应（real-time PCR）和原位杂交技术，研究了几种Wnt配体（Wnt-2、Wnt-3、Wnt-4、Wnt-5a、Wnt-7a和Wnt-8b）、受体[卷曲蛋白（Frizzled，Fz）-6和低密度脂蛋白受体相关蛋白（LRP）-6]、抑制剂[FrpHE和Dickkopf（Dkk）-1]以及下游效应分子（Dishevelled-1、糖原合酶激酶-3β和β-连环蛋白）在子宫内膜中的表达情况。未观察到Wnt配体（Wnt-3除外）、受体或下游效应分子的表达有明显的月经周期依赖性。与分泌期子宫内膜相比，增殖期子宫内膜中Wnt-3的表达增加了4.7倍（P<0.05）。然而，两种抑制剂在月经周期中均表现出显著变化，与增殖期相比，分泌期FrpHE下调了22.2倍（P<0.05），Dkk-1上调了234.3倍（P<0.001）。原位杂交显示，不同Wnt家族基因在人子宫内膜中有细胞特异性表达。Wnt-7a仅在腔上皮中表达，Fz-6和β-连环蛋白在上皮和间质中均有表达，在月经周期中无明显变化。FrpHE和Dkk-1的表达分别局限于增殖期和分泌期的间质中。Wnt家族基因在子宫内膜不同细胞类型中的这些独特表达模式，以及在月经周期增殖期和分泌期抑制剂的差异调节，强烈提示人子宫内膜上皮和间质成分之间存在Wnt信号对话的功能。此外，它们还强调了该家族在子宫内膜发育、分化和着床过程中可能的重要性。
