title: Full Spectrum of Postnatal Tooth Phenotypes in a Novel Irf6 Cleft Lip Model.
abstract: Clefting of the lip, with or without palatal involvement (CLP), is associated with a higher incidence of developmental tooth abnormalities, including hypodontia and supernumerary teeth, aberrant crown and root morphologies, and enamel defects, although the underlying mechanistic link is poorly understood. As most CLP genes are expressed throughout the oral epithelium, the authors hypothesized that the expression of CLP genes may persist in the dental epithelium and thus, in addition to their earlier role in labiopalatine development, may play an important functional role in subsequent tooth patterning and amelogenesis. To address this, the authors generated a unique conditional knockout model involving the major CLP gene, Irf6, that overcomes the previously reported perinatal lethality to enable assessment of any posteruption dental phenotypes. A dental epithelium-specific Irf6 conditional knockout (Irf6-cKO) mouse was generated via a Pitx2-Cre driver line. Dental development was analyzed by microcomputed tomography, scanning electron microscopy, histology, immunohistochemistry, and quantitative polymerase chain reaction. Irf6-cKO mice displayed variable hypodontia, occasional supernumerary incisors and molars, as well as crown and root patterning anomalies, including peg-shaped first molars and taurodontic and C-shaped mandibular second molars. Enamel density was reduced in preeruption Irf6-cKO mice, and some shearing of enamel rods was noted in posteruption incisors. There was also rapid attrition of Irf6-cKO molars following eruption. Histologically, Irf6-cKO ameloblasts exhibited disturbances in adhesion and polarity, and delayed enamel formation was confirmed immunohistochemically. Altered structure of Hertwig's epithelial root sheath was also observed. These data support a role for IRF6 in tooth number, crown and root morphology and amelogenesis that is likely due to a functional role of Irf6 in organization and polarity of epithelial cell types. This data reinforce the notion that various isolated tooth defects could be considered part of the CLP spectrum in relatives of an affected individual.
authors.affiliation: Department of Oral Health Sciences, University of Washington, Seattle, WA, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Chu
authors.affiliation: Department of Oral Health Sciences, University of Washington, Seattle, WA, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Tamasas
authors.affiliation: Department of Materials Science and Engineering, University of Washington, Seattle, WA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Fong
authors.affiliation: Biosciences Division, College of Dentistry, The Ohio State University, Columbus, OH, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Foster
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: LaCourse
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Tran
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, and Texas Heart Institute, Houston, TX, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Martin
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Schutte
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Somerman
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia tccox@uw.edu.
authors.forename: T C
authors.initials: TC
authors.lastname: Cox
mesh_terms: D000566:Amelogenesis / Q000235:genetics; D000818:Animals; D002971:Cleft Lip / Q000150:complications* / Q000000981:diagnostic imaging* / Q000235:genetics; D003743:Dental Enamel / Q000254:growth & development; D004195:Disease Models, Animal; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D010641:Phenotype; D014071:Tooth Abnormalities / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors
keywords: amelogenesis; cleft lip/palate; hypodontia; supernumerary teeth; taurodontism; van der Woude