Canonical Wnt signaling is critical to estrogen-mediated uterine growth.
Major biological effects of estrogen in the uterus are thought to be primarily mediated by nuclear estrogen receptors, ERalpha and ERbeta. We show here that estrogen in an ER-independent manner rapidly up-regulates the expression of Wnt4 and Wnt5a of the Wnt family and frizzled-2 of the Wnt receptor family in the mouse uterus. One of the mechanisms by which Wnts mediate canonical signaling involves stabilization of intracellular beta-catenin. We observed that estrogen treatment prompts nuclear localization of active beta-catenin in the uterine epithelium. We also found that adenovirus mediated in vivo delivery of SFRP-2, a Wnt antagonist, down-regulates estrogen-dependent beta-catenin activity without affecting some of the early effects (water imbibition and angiogenic markers) and inhibits uterine epithelial cell growth, suggesting that canonical Wnt signaling is critical to estrogen-induced uterine growth. Our present results provide evidence for a novel role of estrogen that targets early Wnt/beta-catenin signaling in an ER-independent manner to regulate the late uterine growth response that is ER dependent.
Hou
Xiaonan
X
Department of Pediatrics, D-4105 Medical Center North, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232-2678, USA.
Tan
Yi
Y
Li
Meiling
M
Dey
Sudhansu K
SK
Das
Sanjoy K
SK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism*; D004717:Endometrium / Q000737:chemistry / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000502:physiology; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D014162:Transfection; D014599:Uterus / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; D051176:beta Catenin; D000094742:Secreted Frizzled-Related Proteins
D003598:Cytoskeletal Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D051157:Frizzled Receptors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D015534:Trans-Activators; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C489743:Fzd2 protein, mouse; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C555582:Wnt4 protein, mouse; C438615:Wnt5a protein, mouse