Cytomegalovirus inhibition of embryonic mouse tooth development: a model of the human amelogenesis imperfecta phenocopy.
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.
Jaskoll
Tina
T
Laboratory for Developmental Genetics, University of Southern California, Los Angeles, CA 90089-0641, USA. tjaskoll@usc.edu
Abichaker
George
G
Jangaard
Nolan
N
Bringas
Pablo
P
Melnick
Michael
M
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*
D000998:Antiviral Agents; D016328:NF-kappa B; D000212:Acyclovir