title: Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal.
abstract: Sox2 marks dental epithelial stem cells (DESCs) in both mammals and reptiles, and in this article we demonstrate several Sox2 transcriptional mechanisms that regulate dental stem cell fate and incisor growth. Conditional Sox2 deletion in the oral and dental epithelium results in severe craniofacial defects, including impaired dental stem cell proliferation, arrested incisor development and abnormal molar development. The murine incisor develops initially but is absorbed independently of apoptosis owing to a lack of progenitor cell proliferation and differentiation. Tamoxifen-induced inactivation of Sox2 demonstrates the requirement of Sox2 for maintenance of the DESCs in adult mice. Conditional overexpression of Lef-1 in mice increases DESC proliferation and creates a new labial cervical loop stem cell compartment, which produces rapidly growing long tusk-like incisors, and Lef-1 epithelial overexpression partially rescues the tooth arrest in Sox2 conditional knockout mice. Mechanistically, Pitx2 and Sox2 interact physically and regulate Lef-1, Pitx2 and Sox2 expression during development. Thus, we have uncovered a Pitx2-Sox2-Lef-1 transcriptional mechanism that regulates DESC homeostasis and dental development.
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Yu
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Sanz Navarro
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Mason
authors.initials: M
authors.lastname: Sweat
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Eliason
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Thad
authors.initials: T
authors.lastname: Sharp
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.|State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P.R.China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Orofacial Sciences and Program in Craniofacial Biology, UCSF, San Francisco, CA 94143-0442, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidel
authors.affiliation: State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P.R.China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lynch
authors.affiliation: Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Holton
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rogers
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Traci
authors.initials: T
authors.lastname: Neff
authors.affiliation: Department of Obstetrics and Gynecology, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goodheart
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Michon
authors.affiliation: Department of Orofacial Sciences and Program in Craniofacial Biology, UCSF, San Francisco, CA 94143-0442, USA.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chai
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Dupuy
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
authors.affiliation: State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P.R.China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA brad-amendt@uiowa.edu.|Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Brad A
authors.identifier: 0000-0001-6524-1006
authors.initials: BA
authors.lastname: Amendt
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal / Q000235:genetics*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004848:Epithelium / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007180:Incisor / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009805:Odontogenesis / Q000235:genetics*; D011485:Protein Binding; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C497574:Lef1 protein, mouse; C527783:Sox2 protein, mouse
keywords: Cleft palate; Lef-1; Periderm; Pitx2; Sox2; Stem cells