title: Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a.
abstract: Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.
authors.affiliation: From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China,; the Department of Microbiology, School of Medicine, University of Tokyo, Tokyo 1130033, Japan, and.
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
authors.affiliation: the Children's Hospital and.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Tang
authors.affiliation: From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Wu
authors.affiliation: the Children's Hospital and.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Xiong
authors.affiliation: From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Ruan
authors.affiliation: From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Musaddique
authors.initials: M
authors.lastname: Hussain
authors.affiliation: First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Junsong
authors.initials: J
authors.lastname: Wu
authors.affiliation: the Children's Hospital and. Electronic address: zcc14@zju.edu.cn.
authors.forename: Chaochun
authors.initials: C
authors.lastname: Zou
authors.affiliation: From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China,. Electronic address: xiwu@zju.edu.cn.
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins; D005260:Female; D015686:Gene Products, env / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism; D055550:Protein Stability; D014157:Transcription Factors / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D000075746:Zinc Finger Protein Gli2
chemical_list: D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; C082593:GLI2 protein, human; D015686:Gene Products, env; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011257:Pregnancy Proteins; D014157:Transcription Factors; D000075746:Zinc Finger Protein Gli2; C405335:syncytin
keywords: GCMa; GLI2; Hedgehog signaling pathway; cell fusion; complex; placenta; protein stability; transactivation; trophoblast