Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKβ, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkβ). K5-Ikkβ mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkβ mice. The supernumerary incisors in K5-Ikkβ mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.

Craniofacial Development and Stem Cell Biology and Biomedical Research Centre Kings College London London UK

Craniofacial Development and Stem Cell Biology and Biomedical Research Centre Kings College London London UK Department of Pediatric Dentistry Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

Craniofacial Development and Stem Cell Biology and Biomedical Research Centre Kings College London London UK Department of Physiology Faculty of Dentistry Chulalongkorn University Bangkok Thailand

Craniofacial Development and Stem Cell Biology and Biomedical Research Centre Kings College London London UK Department of Special Needs Dentistry Nihon University School of Dentistry at Matsudo Matsudo Japan

Craniofacial Development and Stem Cell Biology and Biomedical Research Centre Kings College London London UK Division of Bio Prosthodontics Department of Oral Health Science Course for Oral Life Science Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

Craniofacial Development and Stem Cell Biology and Biomedical Research Centre Kings College London London UK Division of Oral Anatomy Department of Oral Biological Science Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

Department of Epithelial Biomedicine Centro de Investigaciones Energéticas Medioambientales y Tecnológicas Madrid Spain

Department of Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Smithville TX USA

Department of Signal Transduction in Tumor Cells Max Delbrück Center for Molecular Medicine Berlin Germany

Department of Special Needs Dentistry Nihon University School of Dentistry at Matsudo Matsudo Japan

Department of Teratology Institute of Experimental Medicine Academy of Sciences CR Prague Czech Republic

Department of Ultrastructural Science Tokyo Dental College Chiyoda ku Tokyo Japan

Division of Cellular and Molecular Biology Institute of Medical Science University of Tokyo Minato ku Tokyo Japan

Division of Oral Anatomy Department of Oral Biological Science Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

INSERM UMR_S1109 Team Osteoarticular and Dental Regenerative NanoMedicine FMTS Faculté de Médecine Faculté de Chirurgie Dentaire Université de Strasbourg Strasbourg France

Laboratory of Experimental Immunology Inflammation and Tumorigenesis Section National Cancer Institute Frederick Frederick MD USA

Laboratory of Food Biological Science Department of Food and Nutrition Japan Women's University Bunkyō Japan

See more in PubMed

Ahn Y, Sanderson BW, Klein OD, Krumlauf R. 2010. Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development. 137(19):3221–3231. PubMed PMC

Asher RJ, Meng J, Wible JR, McKenna MC, Rougier GW, Dashzeveg D, Novacek MJ. 2005. Stem lagomorpha and the antiquity of Glires. Science. 307(5712):1091–1094. PubMed

Blackburn J, Ohazama A, Kawasaki K, Otsuka-Tanaka Y, Liu B, Honda K, Rountree RB, Hu Y, Kawasaki M, Birchmeier W, et al. 2012. The role of Irf6 in tooth epithelial invagination. Dev Biol. 365(1):61–70. PubMed PMC

Charles C, Hovorakova M, Ahn Y, Lyons DB, Marangoni P, Churava S, Biehs B, Jheon A, Lesot H, Balooch G, et al. 2011. Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling. Development. 138(18):4063–4073. PubMed PMC

Harada H, Kettunen P, Jung HS, Mustonen T, Wang YA, Thesleff I. 1999. Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling. J Cell Biol. 147(1):105–120. PubMed PMC

Hirschfeld Z, Weinreb MM, Michaeli Y. 1973. Incisors of the rabbit: morphology, histology, and development. J Dent Res. 52(2):377–384. PubMed

Järvinen E, Salazar-Ciudad I, Birchmeier W, Taketo MM, Jernvall J, Thesleff I. 2006. Continuous tooth generation in mouse is induced by activated epithelial Wnt/beta-catenin signaling. Proc Natl Acad Sci USA. 103(49):18627–18632. PubMed PMC

Kaler P, Godasi BN, Augenlicht L, Klampfer L. 2009. The NF-kappaB/AKT-dependent induction of Wnt signaling in colon cancer cells by macrophages and IL-1beta. Cancer Microenviron. 2:69–80. PubMed PMC

Kassai Y, Munne P, Hotta Y, Penttilä E, Kavanagh K, Ohbayashi N, Takada S, Thesleff I, Jernvall J, Itoh N. 2005. Regulation of mammalian tooth cusp patterning by ectodin. Science. 309(5743):2067–2070. PubMed

Lapthanasupkul P, Feng J, Mantesso A, Takada-Horisawa Y, Vidal M, Koseki H, Wang L, An Z, Miletich I, Sharpe PT. 2012. Ring1a/b polycomb proteins regulate the mesenchymal stem cell niche in continuously growing incisors. Dev Biol. 367(2):140–153. PubMed

Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y, Sun HL, Li LY, Ping B, Huang WC, et al. 2007. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell. 130(3):440–455. PubMed

Lesot H, Vonesch JL, Peterka M, Turecková J, Peterková R, Ruch JV. 1996. Mouse molar morphogenesis revisited by three-dimensional reconstruction. II. Spatial distribution of mitoses and apoptosis in cap to bell staged first and second upper molar teeth. Int J Dev Biol. 40(5):1017–1031. PubMed

Liu F, Dangaria S, Andl T, Zhang Y, Wright AC, Damek-Poprawa M, Piccolo S, Nagy A, Taketo MM, Diekwisch TG, et al. 2010. beta-Catenin initiates tooth neogenesis in adult rodent incisors. J Dent Res. 89(9):909–914. PubMed PMC

Lomada D, Liu B, Coghlan L, Hu Y, Richie ER. 2007. Thymus medulla formation and central tolerance are restored in IKKalpha-/- mice that express an IKKalpha transgene in keratin 5+ thymic epithelial cells. J Immunol. 178(2):829–837. PubMed

Mikkola ML, Thesleff I. 2003. Ectodysplasin signaling in development. Cytokine Growth Factor Rev. 14(3-4): 211–224. PubMed

Munne PM, Tummers M, Järvinen E, Thesleff I, Jernvall J. 2009. Tinkering with the inductive mesenchyme: Sostdc1 uncovers the role of dental mesenchyme in limiting tooth induction. Development. 136(3):393–402. PubMed

Murashima-Suginami A, Takahashi K, Kawabata T, Sakata T, Tsukamoto H, Sugai M, Yanagita M, Shimizu A, Sakurai T, Slavkin HC, et al. 2007. Rudiment incisors survive and erupt as supernumerary teeth as a result of USAG-1 abrogation. Biochem Biophys Res Commun. 359(3):549–555. PubMed

Mustonen T, Pispa J, Mikkola ML, Pummila M, Kangas AT, Pakkasjärvi L, Jaatinen R, Thesleff I. 2003. Stimulation of ectodermal organ development by ectodysplasin-A1. Dev Biol. 259(1):123–136. PubMed

Oeckinghaus A, Hayden MS, Ghosh S. 2011. Crosstalk in NF-κB signaling pathways. Nat Immunol. 12(8):695–708. PubMed

Ohazama A, Hu Y, Schmidt-Ullrich R, Cao Y, Scheidereit C, Karin M, Sharpe PT. 2004. A dual role for Ikk alpha in tooth development. Dev Cell. 6(2):219–227. PubMed

Ohazama A, Johnson EB, Ota MS, Choi HY, Porntaveetus T, Oommen S, Itoh N, Eto K, Gritli-Linde A, Herz J, et al. 2008. Lrp4 modulates extracellular integration of cell signaling pathways in development. PLoS One. 3(12):e4092. PubMed PMC

Page A, Navarro M, Garín M, Pérez P, Casanova ML, Moreno R, Jorcano JL, Cascallana JL, Bravo A, Ramírez A. 2010. IKKbeta leads to an inflammatory skin disease resembling interface dermatitis. J Invest Dermatol. 130(6):1598–1610. PubMed

Peterková R1, Kristenová P, Lesot H, Lisi S, Vonesch JL, Gendrault JL, Peterka M. 2002. Different morphotypes of the tabby (EDA) dentition in the mouse mandible result from a defect in the mesio-distal segmentation of dental epithelium. Orthod Craniofac Res. 5(4):215–226. PubMed

Rose KD, Archibald JD. 2005. The rise of placental mammals: origins and relationships of the major extant clades. Rose KD, Archibald JD, editors. Baltimore (MD): Johns Hopkins University Press.

Satokata I, Maas R. 1994. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet. 6(4):348–356. PubMed

Schmidt-Ullrich R, Aebischer T, Hülsken J, Birchmeier W, Klemm U, Scheidereit C. 2001. Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development. 128(19):3843–3853. PubMed

Schmidt-Ullrich R, Mémet S, Lilienbaum A, Feuillard J, Raphaël M, Israel A. 1996. NF-kappaB activity in transgenic mice: developmental regulation and tissue specificity. Development. 122(7):2117–2128. PubMed

Suomalainen M, Thesleff I. 2010. Patterns of Wnt pathway activity in the mouse incisor indicate absence of Wnt/beta-catenin signaling in the epithelial stem cells. Dev Dyn. 239(1):364–372. PubMed

Xia Y, Padre RC, De Mendoza TH, Bottero V, Tergaonkar VB, Verma IM. 2009. Phosphorylation of p53 by IkappaB kinase 2 promotes its degradation by beta-TrCP. Proc Natl Acad Sci USA. 106(8):2629–2634. PubMed PMC

Zhang Z, Lan Y, Chai Y, Jiang R. 2009. Antagonistic actions of Msx1 and Osr2 pattern mammalian teeth into a single row. Science. 323(5918):1232–1234. PubMed PMC

Role of Cell Death in Cellular Processes During Odontogenesis