title: Cytomegalovirus inhibition of embryonic mouse tooth development: a model of the human amelogenesis imperfecta phenocopy.
abstract: OBJECTIVE
  Cytomegalovirus (CMV) is one of the most common causes of major birth defects in humans. Of the approximately 8400 children born each year in the U.S. with CMV-induced birth defects, more than 1/3 of these children exhibit hypoplasia and hypocalcification of tooth enamel. Our objective was to initiate the investigation of the pathogenesis of CMV-induced tooth defects.
  
  
  METHODS
  Mouse Cap stage mandibular first molars were infected with mouse CMV (mCMV) in vitro in a chemically-defined organ culture system and analysed utilising histological and immunolocalisation methodologies. The antiviral, acyclovir, was used to inhibit mCMV replication and comparisons made between mCMV-infected and acyclovir-treated, mCMV-infected teeth.
  
  
  RESULTS
  Active infection of Cap stage molars for up to 15 days in vitro results in smaller, developmentally-delayed and dysmorphic molars characterised by shallow, broad and misshapen cusps, infected and affected dental papilla mesenchyme, poorly differentiated odontoblasts and ameloblasts, and no dentin matrix. Initial protein localisation studies suggest that the pathogenesis is mediated through NF-kappaB signaling and that there appears to be an unusual interaction between abnormal mesenchymal cells and surrounding matrix. Rescue with acyclovir indicates that mCMV replication is necessary to initiate and sustain progressive tooth dysmorphogenesis.
  
  
  CONCLUSIONS
  Our results indicate that mCMV-induced changes in signaling pathways severely delays, but does not completely interrupt, tooth morphogenesis. Importantly, our results demonstrate that this well-defined embryonic mouse organ culture system can be utilised to delineate the molecular mechanism underlying the CMV-induced tooth defects that characterise the amelogenesis imperfecta phenocopy seen in many CMV-infected children.
authors.affiliation: Laboratory for Developmental Genetics, University of Southern California, Los Angeles, CA 90089-0641, USA. tjaskoll@usc.edu
authors.forename: Tina
authors.initials: T
authors.lastname: Jaskoll
authors.forename: George
authors.initials: G
authors.lastname: Abichaker
authors.forename: Nolan
authors.initials: N
authors.lastname: Jangaard
authors.forename: Pablo
authors.initials: P
authors.lastname: Bringas
authors.forename: Michael
authors.initials: M
authors.lastname: Melnick
mesh_terms: D000212:Acyclovir / Q000627:therapeutic use; D000565:Ameloblasts; D000567:Amelogenesis Imperfecta / Q000196:embryology* / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology; D006566:Herpesviridae Infections; D006801:Humans; D051379:Mice; D018146:Muromegalovirus; D016328:NF-kappa B / Q000378:metabolism; D009804:Odontoblasts; D009805:Odontogenesis; D014070:Tooth / Q000196:embryology / Q000378:metabolism; D014083:Tooth Germ / Q000196:embryology / Q000821:virology*
chemical_list: D000998:Antiviral Agents; D016328:NF-kappa B; D000212:Acyclovir