Analysis of the Role of Sprouty Genes in Tooth Development

Summary

Principal Investigator: Ophir Klein
Abstract: The study of the developmental regulation of tooth number and shape is important for understanding human disease. Mammalian tooth development is controlled by signaling between the oral epithelium and the neural crest-derived ectomesenchyme. These interactions are mediated by several signaling pathways, including those activated by Fibroblast Growth Factors (FGFs) via binding to FGF receptor- tyrosine kinases. Members of the Sprouty family modulate FGF signaling by antagonizing it downstream of the receptor. In my previous work, I have shown that inactivation of Spry2 or Spry4 results in the formation of supernumerary teeth in the diastema, a normally toothless region between the incisors and molars of mice. These supernumerary teeth result from hypersensitivity of the odontogenic epithelium or mesenchyme to FGF signaling. In this application, I will pursue the observation that inactivation of multiple Sprouty alleles has profound effects on incisor development. Embryos that are null for Spry4 and heterozygous for Spry2 have supernumerary incisors in the maxilla and remarkable tusk-like incisors in the mandible. Embryos that are null for two Sprouty genes also develop supernumerary incisors, although the morphology of these incisors varies depending on the genotype. The first group of experiments will test the hypothesis that the tusk-like incisor phenotype is caused by effects on stem cells in the adult incisor. I will analyze the role of FGFs and other signaling molecules in regulation of incisor stem cells. The second group of experiments in this proposal is aimed at elucidating the normal mechanisms that control the number and morphology of incisors, as well as the role of Sprouty genes in these processes. Results from these studies will enhance our understanding of the molecular pathways that control epithelial-mesenchymal interactions during tooth organogenesis and may help lead to innovative treatments for patients with dental defects, including even the possibility of bioengineering new teeth. The studies proposed here employ a genetic approach to determine the functions of the Sprouty (Spry) genes in mouse tooth development. Public health implications: By studying the functions of the Sprouty gene family, we will learn more about how teeth normally develop and will understand more about the basis for dental abnormalities. We will also study the role of adult stem cells in teeth, which may help to lay the groundwork for efforts to build new teeth.
Funding Period: 2007-07-01 - 2012-06-30
more information: NIH RePORT

Top Publications

  1. pmc E-cadherin regulates the behavior and fate of epithelial stem cells and their progeny in the mouse incisor
    Chun Ying Li
    Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, UCSF, USA
    Dev Biol 366:357-66. 2012
  2. pmc Temporal analysis of ectopic enamel production in incisors from sprouty mutant mice
    Tomas Boran
    Department of Teratology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    J Exp Zool B Mol Dev Evol 312:473-85. 2009
  3. pmc Revitalization of a diastemal tooth primordium in Spry2 null mice results from increased proliferation and decreased apoptosis
    Renata Peterkova
    Department of Teratology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    J Exp Zool B Mol Dev Evol 312:292-308. 2009
  4. pmc Enamel-free teeth: Tbx1 deletion affects amelogenesis in rodent incisors
    Javier Caton
    Department of Craniofacial Development, King s College London, GKT Dental Institute, London SE1 9RT, UK
    Dev Biol 328:493-505. 2009
  5. pmc Modulation of Fgf3 dosage in mouse and men mirrors evolution of mammalian dentition
    Cyril Charles
    Department of Orofacial Sciences, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 0442, USA
    Proc Natl Acad Sci U S A 106:22364-8. 2009

Scientific Experts

  • Renata Peterkova
  • Chun Ying Li
  • Hans Ulrich Luder
  • Ophir D Klein
  • Thimios A Mitsiadis
  • Javier Caton
  • Ophir Klein
  • Cyril Charles
  • Tomas Boran
  • Roch Philippe Charles
  • Martin McMahon
  • Wanghee Cha
  • Matthew Bradman
  • Mustafa Tekin
  • Herve Lesot
  • Miroslav Peterka
  • Laurent Viriot
  • Abigail S Tucker
  • Vincent Lazzari
  • Maria Zoupa
  • Gilles Bluteau
  • David B Lyons
  • Thomas Schimmang
  • Paul Tafforeau

Detail Information

Publications5

  1. pmc E-cadherin regulates the behavior and fate of epithelial stem cells and their progeny in the mouse incisor
    Chun Ying Li
    Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, UCSF, USA
    Dev Biol 366:357-66. 2012
    ..Together, our data indicate that E-cadherin is an important regulator of stem cells and their progeny during growth of the mouse incisor...
  2. pmc Temporal analysis of ectopic enamel production in incisors from sprouty mutant mice
    Tomas Boran
    Department of Teratology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    J Exp Zool B Mol Dev Evol 312:473-85. 2009
    ....
  3. pmc Revitalization of a diastemal tooth primordium in Spry2 null mice results from increased proliferation and decreased apoptosis
    Renata Peterkova
    Department of Teratology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    J Exp Zool B Mol Dev Evol 312:292-308. 2009
    ..Studies of the revitalization of rudimentary tooth primordia in mutant mice can help to lay the foundation for tooth regeneration by enhancing our knowledge of mechanisms that regulate tooth formation...
  4. pmc Enamel-free teeth: Tbx1 deletion affects amelogenesis in rodent incisors
    Javier Caton
    Department of Craniofacial Development, King s College London, GKT Dental Institute, London SE1 9RT, UK
    Dev Biol 328:493-505. 2009
    ..These results demonstrate that Tbx1 is essential for the maintenance of ameloblast progenitor cells in rodent incisors and that its deletion results in the absence of enamel formation...
  5. pmc Modulation of Fgf3 dosage in mouse and men mirrors evolution of mammalian dentition
    Cyril Charles
    Department of Orofacial Sciences, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 0442, USA
    Proc Natl Acad Sci U S A 106:22364-8. 2009
    ..We anticipate that our multidisciplinary study will advance the detailed correlation of subtle dental modifications with genetic mutations in a variety of mammalian lineages...