title: A positive feedback loop involving Gcm1 and Fzd5 directs chorionic branching morphogenesis in the placenta.
abstract: Chorioallantoic branching morphogenesis is a key milestone during placental development, creating the large surface area for nutrient and gas exchange, and is therefore critical for the success of term pregnancy. Several Wnt pathway molecules have been shown to regulate placental development. However, it remains largely unknown how Wnt-Frizzled (Fzd) signaling spatiotemporally interacts with other essential regulators, ensuring chorionic branching morphogenesis and angiogenesis during placental development. Employing global and trophoblast-specific Fzd5-null and Gcm1-deficient mouse models, combining trophoblast stem cell lines and tetraploid aggregation assay, we demonstrate here that an amplifying signaling loop between Gcm1 and Fzd5 is essential for normal initiation of branching in the chorionic plate. While Gcm1 upregulates Fzd5 specifically at sites where branching initiates in the basal chorion, this elevated Fzd5 expression via nuclear β-catenin signaling in turn maintains expression of Gcm1. Moreover, we show that Fzd5-mediated signaling induces the disassociation of cell junctions for branching initiation via downregulating ZO-1, claudin 4, and claudin 7 expressions in trophoblast cells at the base of the chorion. In addition, Fzd5-mediated signaling is also important for upregulation of Vegf expression in chorion trophoblast cells. Finally, we demonstrate that Fzd5-Gcm1 signaling cascade is operative during human trophoblast differentiation. These data indicate that Gcm1 and Fzd5 function in an evolutionary conserved positive feedback loop that regulates trophoblast differentiation and sites of chorionic branching morphogenesis.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Lu
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Haruo
authors.initials: H
authors.lastname: Nakano
authors.forename: David G
authors.initials: DG
authors.lastname: Simmons
authors.forename: Shumin
authors.initials: S
authors.lastname: Wang
authors.forename: Shuangbo
authors.initials: S
authors.lastname: Kong
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Lianju
authors.initials: L
authors.lastname: Shen
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Tu
authors.forename: Weixiang
authors.initials: W
authors.lastname: Wang
authors.forename: Bingyan
authors.initials: B
authors.lastname: Wang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wang
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: James C
authors.initials: JC
authors.lastname: Cross
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049033:Chorioallantoic Membrane / Q000254:growth & development / Q000378:metabolism; D002824:Chorionic Villi / Q000254:growth & development* / Q000378:metabolism; D004268:DNA-Binding Proteins; D025461:Feedback, Physiological; D005260:Female; D051157:Frizzled Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D015726:Giant Cells / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000098:blood supply / Q000166:cytology; D010929:Placentation; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000502:physiology; D060449:Wnt Signaling Pathway
chemical_list: D004268:DNA-Binding Proteins; C498589:FZD5 protein, human; D051157:Frizzled Receptors; C491089:GCM1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors