title: The Pitx2:miR-200c/141:noggin pathway regulates Bmp signaling and ameloblast differentiation.
abstract: The mouse incisor is a remarkable tooth that grows throughout the animal's lifetime. This continuous renewal is fueled by adult epithelial stem cells that give rise to ameloblasts, which generate enamel, and little is known about the function of microRNAs in this process. Here, we describe the role of a novel Pitx2:miR-200c/141:noggin regulatory pathway in dental epithelial cell differentiation. miR-200c repressed noggin, an antagonist of Bmp signaling. Pitx2 expression caused an upregulation of miR-200c and chromatin immunoprecipitation assays revealed endogenous Pitx2 binding to the miR-200c/141 promoter. A positive-feedback loop was discovered between miR-200c and Bmp signaling. miR-200c/141 induced expression of E-cadherin and the dental epithelial cell differentiation marker amelogenin. In addition, miR-203 expression was activated by endogenous Pitx2 and targeted the Bmp antagonist Bmper to further regulate Bmp signaling. miR-200c/141 knockout mice showed defects in enamel formation, with decreased E-cadherin and amelogenin expression and increased noggin expression. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR-200c/141:noggin regulatory pathway that is important in epithelial cell differentiation and tooth development.
authors.affiliation: Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Huojun
authors.initials: H
authors.lastname: Cao
authors.forename: Andrew
authors.initials: A
authors.lastname: Jheon
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Zhao
authors.initials: Z
authors.lastname: Sun
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: Sergio
authors.initials: S
authors.lastname: Florez
authors.forename: Zichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.forename: Brad A
authors.initials: BA
authors.lastname: Amendt
mesh_terms: D053523:Amelogenin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D003743:Dental Enamel / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007180:Incisor / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000097577:Homeobox Protein PITX2; D000099176:Noggin Protein
chemical_list: D053523:Amelogenin; D052005:Bone Morphogenetic Protein Receptors, Type I; D015820:Cadherins; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D051898:Smad1 Protein; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; D000099176:Noggin Protein; C543718:Mirn141 microRNA, mouse; C543719:Mirn200 microRNA, mouse; C497401:Smad1 protein, mouse; C517553:crossveinless 2 protein, mouse; C498212:Bmpr1a protein, mouse
keywords: Bmp; Noggin; Pitx2; Stem cells; Tooth development; miR-141; miR-200 family; miR-200c; miR-203