title: N-myc controls proliferation, morphogenesis, and patterning of the inner ear.
abstract: Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27(Kip1) and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.
authors.affiliation: Institute of Biology and Molecular Genetics, University of Valladolid and Spanish National Research Council, E-47003 Valladolid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Domínguez-Frutos
authors.forename: Iris
authors.initials: I
authors.lastname: López-Hernández
authors.forename: Victor
authors.initials: V
authors.lastname: Vendrell
authors.forename: Joana
authors.initials: J
authors.lastname: Neves
authors.forename: Micaela
authors.initials: M
authors.lastname: Gallozzi
authors.forename: Katja
authors.initials: K
authors.lastname: Gutsche
authors.forename: Laura
authors.initials: L
authors.lastname: Quintana
authors.forename: James
authors.initials: J
authors.lastname: Sharpe
authors.forename: Paul S
authors.initials: PS
authors.lastname: Knoepfler
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Fernando
authors.initials: F
authors.lastname: Giráldez
authors.forename: Thomas
authors.initials: T
authors.lastname: Schimmang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D007758:Ear, Inner / Q000196:embryology* / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016271:Proto-Oncogene Proteins c-myc