title: Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth.
abstract: During inner ear development programmed cell death occurs in specific areas of the otic epithelium but the significance of it and the molecules involved have remained unclear. We undertook an analysis of mouse mutants in which genes encoding apoptosis-associated molecules have been inactivated. Disruption of the Apaf1 gene led to a dramatic decrease in apoptosis in the inner ear epithelium, severe morphogenetic defects and a significant size reduction of the membranous labyrinth, demonstrating that an Apaf1-dependent apoptotic pathway is necessary for normal inner ear development. This pathway most probably operates through the apoptosome complex because caspase 9 mutant mice suffered similar defects. Inactivation of the Bcl2-like (Bcl2l) gene led to an overall increase in the number of cells undergoing apoptosis but did not cause any major morphogenetic defects. In contrast, decreased apoptosis was observed in specific locations that suffered from developmental deficits, indicating that proapoptotic isoform(s) produced from Bcl2l might have roles in inner ear development. In Apaf1(-/-)/Bcl2l(-/-) double mutant embryos, no cell death could be detected in the otic epithelium, demonstrating that the cell death regulated by the anti-apoptotic Bcl2l isoform, Bcl-X(L) in the otic epithelium is Apaf1-dependent. Furthermore, the otic vesicle failed to close completely in all double mutant embryos analyzed. These results indicate important roles for both Apaf1 and Bcl2l in inner ear development.
authors.affiliation: Dulbecco Telethon Institute, Department of Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, 00133 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: Oleg
authors.initials: O
authors.lastname: Dolgov
authors.forename: Eliana
authors.initials: E
authors.lastname: Munarriz
authors.forename: Konstantin
authors.initials: K
authors.lastname: Anokhin
authors.forename: Peter
authors.initials: P
authors.lastname: Gruss
authors.forename: Marjo
authors.initials: M
authors.lastname: Salminen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D007758:Ear, Inner / Q000002:abnormalities / Q000033:anatomy & histology / Q000196:embryology* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005865:Gestational Age; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; C494812:Bcl2l1 protein, mouse; D020033:Protein Isoforms; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases