title: An in vitro mouse model of congenital cytomegalovirus-induced pathogenesis of the inner ear cochlea.
abstract: Congenital human cytomegalovirus (CMV) infection is the leading nongenetic etiology of sensorineural hearing loss (SNHL) at birth and prelingual SNHL not expressed at birth. The paucity of temporal bone autopsy specimens from infants with congenital CMV infection has hindered the critical correlation of histopathology with pathogenesis. Here, we present an in vitro embryonic mouse model of CMV-infected cochleas that mimics the human sites of viral infection and associated pathology. There is a striking dysplasia/hyperplasia in mouse CMV-infected cochlear epithelium and mesenchyme, including organ of Corti hair and supporting cells and stria vascularis. This is concomitant with significant dysregulation of p19, p21, p27, and Pcna gene expression, as well as proliferating cell nuclear antigen (PCNA) protein expression. Other pathologies similar to those arising from known deafness gene mutations include downregulation of KCNQ1 protein expression in the stria vascularis, as well as hypoplastic and dysmorphic melanocytes. Thus, this model provides a relevant and reliable platform within which the detailed cell and molecular biology of CMV-induced deafness may be studied.
authors.affiliation: Laboratory for Developmental Genetics, University of Southern California, Los Angeles, CA 90089, USA. mmelnick@usc.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Melnick
authors.forename: Tina
authors.initials: T
authors.lastname: Jaskoll
mesh_terms: D000818:Animals; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000235:genetics* / Q000473:pathology*; D006566:Herpesviridae Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D007223:Infant; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018146:Muromegalovirus / Q000502:physiology; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000002:abnormalities* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D013316:Stria Vascularis / Q000378:metabolism / Q000473:pathology*
chemical_list: C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen