title: CDH1 is essential for endometrial differentiation, gland development, and adult function in the mouse uterus.
abstract: CDH1 is a cell-cell adhesion molecule expressed in the epithelium to coordinate key morphogenetic processes, establish cell polarity, and regulate epithelial differentiation and proliferation. To determine the role of CDH1 in the mouse uterus, Cdh1 was conditionally ablated by crossing Pgr-Cre and Cdh1-flox mice, and the phenotype was characterized. We found that loss of Cdh1 results in a disorganized cellular structure of the epithelium and ablation of endometrial glands in the neonatal uterus. Cdh1(d/d) mice lost adherens junctions (CTNNB1 and CTNNA1) and tight junctions (claudin, occludin, and ZO-1 proteins) in the neonatal uterus, leading to loss of epithelial cell-cell interaction. Ablation of Cdh1 induced abnormal epithelial proliferation and massive apoptosis, and disrupted Wnt and Hox gene expression in the neonatal uterus. Although the uteri of Cdh1(d/d) mice did not show any myometrial defects, ablation of Cdh1 inhibited expression of epithelial (cytokeratin 8) and stromal (CD10) markers. Cdh1(d/d) mice were infertile because of defects during implantation and decidualization. Furthermore, we showed in the model of conditional ablation of both Cdh1 and Trp53 in the uterus that interrupting cell cycle regulation through the loss of Cdh1 leads to abnormal uterine development. The uteri of Cdh1(d/d) Trp53(d/d) mice exhibited histological features of endometrial carcinomas with myometrial invasion. Collectively, these findings suggest that CDH1 has an important role in structural and functional development of the uterus as well as adult uterine function. CDH1 has a capacity to control cell fate by altering directional cell proliferation and apoptosis.
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Reardon
authors.forename: Mandy L
authors.initials: ML
authors.lastname: King
authors.forename: James A
authors.initials: JA
authors.lastname: MacLean
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Mann
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.forename: Kanako
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D022005:Adherens Junctions; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D057167:Claudins / Q000502:physiology; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004717:Endometrium / Q000166:cytology / Q000254:growth & development* / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000502:physiology; D053533:Keratin-8 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D015260:Neprilysin / Q000096:biosynthesis; D062793:Occludin; D010750:Phosphoproteins / Q000502:physiology; D019108:Tight Junctions; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014599:Uterus / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology; D062826:Zonula Occludens-1 Protein; D051178:alpha Catenin / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: C495267:CTNNB1 protein, mouse; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D057167:Claudins; C577585:Fzr1 protein, mouse; D018398:Homeodomain Proteins; D053533:Keratin-8; C486595:Krt8 protein, mouse; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; D016159:Tumor Suppressor Protein p53; D062826:Zonula Occludens-1 Protein; D051178:alpha Catenin; D051176:beta Catenin; D015260:Neprilysin