title: Age-related changes in cochlear gene expression in normal and shaker 2 mice.
abstract: The vertebrate cochlea is a complex organ optimized for sound transduction. Auditory hair cells, with their precisely arranged stereocilia bundles, transduce sound waves to electrical signals that are transmitted to the brain. Mutations in the unconventional myosin XV cause deafness in both human DFNB3 families and in shaker 2 (sh2) mice as a result of defects in stereocilia. In these mutant mice, hair cells have relatively normal spatial organization of stereocilia bundles but lack the graded, stair-step organization. We used sh2 mice as an experimental model to investigate the molecular consequences of the sh2 mutation in the Myo15 gene. Gene expression profiling with Affymetrix GeneChips in deaf homozygous (sh2/sh2) mice at 3 weeks and 3 months of age, and in age-matched, normal-hearing heterozygotes (+/sh2) identified only a few genes whose expression was affected by genotype, but a large number with age-associated changes in expression in both normal mice and sh2/sh2 homozygotes. Microarray data analyzed using Robust Multiarray Average identified Aim1, Dbi, and Tm4sf3 as genes with increased expression in sh2/sh2 homozygotes. These increases were confirmed by quantitative reverse transcription-polymerase chain reaction. Genes exhibiting altered expression with age encoded collagens and proteins involved in collagen maturation, extracellular matrix, and bone mineralization. These results identified potential cellular pathways associated with myosin XV defects, and age-associated molecular events that are likely to be involved in maturation of the cochlea and auditory function.
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology/Head-Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109-0648, USA.
authors.forename: Tzy-Wen L
authors.initials: TW
authors.lastname: Gong
authors.forename: I Jill
authors.initials: IJ
authors.lastname: Karolyi
authors.forename: James
authors.initials: J
authors.lastname: Macdonald
authors.forename: Lisa
authors.initials: L
authors.lastname: Beyer
authors.forename: Yehoash
authors.initials: Y
authors.lastname: Raphael
authors.forename: David C
authors.initials: DC
authors.lastname: Kohrman
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.forename: Margaret I
authors.initials: MI
authors.lastname: Lomax
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology; D034381:Hearing Loss / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009218:Myosins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D050809:POU Domain Factors / Q000235:genetics
chemical_list: C114013:Myo15 protein, mouse; D050809:POU Domain Factors; C091774:POU3F4 protein, human; D009218:Myosins