title: Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene.
abstract: Pou4f3 (Brn3.1, Brn3c) is a class IV POU domain transcription factor that has a central function in the development of all hair cells in the human and mouse inner ear sensory epithelia. A mutation of POU4F3 underlies human autosomal dominant non-syndromic progressive hearing loss DFNA15. Through a comparison of inner ear gene expression profiles of E16.5 wild-type and Pou4f3 mutant deaf mice using a high density oligonucleotide microarray, we identified the gene encoding growth factor independence 1 (Gfi1) as a likely in vivo target gene regulated by Pou4f3. To validate this result, we performed semi-quantitative RT-PCR and in situ hybridizations for Gfi1 on wild-type and Pou4f3 mutant mice. Our results demonstrate that a deficiency of Pou4f3 leads to a statistically significant reduction in Gfi1 expression levels and that the dynamics of Gfi1 mRNA abundance closely follow the pattern of expression for Pou4f3. To examine the role of Gfi1 in the pathogenesis of Pou4f3-related deafness, we performed comparative analyses of the embryonic inner ears of Pou4f3 and Gfi1 mouse mutants using immunohistochemistry and scanning electron microscopy. The loss of Gfi1 results in outer hair cell degeneration, which appears comparable to that observed in Pou4f3 mutants. These results identify Gfi1 as the first downstream target of a hair cell specific transcription factor and suggest that outer hair cell degeneration in Pou4f3 mutants is largely or entirely a result of the loss of expression of Gfi1.
authors.affiliation: Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ronna
authors.initials: R
authors.lastname: Hertzano
authors.forename: Mireille
authors.initials: M
authors.lastname: Montcouquiol
authors.forename: Sharon
authors.initials: S
authors.lastname: Rashi-Elkeles
authors.forename: Rani
authors.initials: R
authors.lastname: Elkon
authors.forename: Raif
authors.initials: R
authors.lastname: Yücel
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kelley
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000235:genetics*; D007758:Ear, Inner / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D006198:Hair Cells, Auditory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism; D050821:Transcription Factor Brn-3C; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D018398:Homeodomain Proteins; C121290:Pou4f3 protein, mouse; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050821:Transcription Factor Brn-3C; D014157:Transcription Factors