title: The non-canonical BMP and Wnt/β-catenin signaling pathways orchestrate early tooth development.
abstract: BMP and Wnt signaling pathways play a crucial role in organogenesis, including tooth development. Despite extensive studies, the exact functions, as well as if and how these two pathways act coordinately in regulating early tooth development, remain elusive. In this study, we dissected regulatory functions of BMP and Wnt pathways in early tooth development using a transgenic noggin (Nog) overexpression model (K14Cre;pNog). It exhibits early arrested tooth development, accompanied by reduced cell proliferation and loss of odontogenic fate marker Pitx2 expression in the dental epithelium. We demonstrated that overexpression of Nog disrupted BMP non-canonical activity, which led to a dramatic reduction of cell proliferation rate but did not affect Pitx2 expression. We further identified a novel function of Nog by inhibiting Wnt/β-catenin signaling, causing loss of Pitx2 expression. Co-immunoprecipitation and TOPflash assays revealed direct binding of Nog to Wnts to functionally prevent Wnt/β-catenin signaling. In situ PLA and immunohistochemistry on Nog mutants confirmed in vivo interaction between endogenous Nog and Wnts and modulation of Wnt signaling by Nog in tooth germs. Genetic rescue experiments presented evidence that both BMP and Wnt signaling pathways contribute to cell proliferation regulation in the dental epithelium, with Wnt signaling also controlling the odontogenic fate. Reactivation of both BMP and Wnt signaling pathways, but not of only one of them, rescued tooth developmental defects in K14Cre;pNog mice, in which Wnt signaling can be substituted by transgenic activation of Pitx2. Our results reveal the orchestration of non-canonical BMP and Wnt/β-catenin signaling pathways in the regulation of early tooth development.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Yuan
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
authors.forename: Guobin
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA Department of Periodontology, College of Stomatology, Fujian Medical University, Fuzhou 350002, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institute of Developmental and Regenerative Biology, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 311121, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Developmental and Regenerative Biology, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 311121, China.
authors.forename: Zunyi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA ychen@tulane.edu.
authors.forename: YiPing
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology; D008822:Mice, Transgenic; D008954:Models, Biological; D009805:Odontogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D014070:Tooth / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D014083:Tooth Germ / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000097577:Homeobox Protein PITX2; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D019426:Integrases; D051957:MSX1 Transcription Factor; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097577:Homeobox Protein PITX2; D000099176:Noggin Protein; C484084:Msx1 protein, mouse; C045073:Cre recombinase
keywords: BMP; Development; Mouse; Noggin; Tooth; Wnt