title: Caprin-1 is a target of the deafness gene Pou4f3 and is recruited to stress granules in cochlear hair cells in response to ototoxic damage.
abstract: The POU4 family of transcription factors are required for survival of specific cell types in different sensory systems. Pou4f3 is essential for the survival of auditory sensory hair cells and several mutations in human POU4F3 cause hearing loss. Thus, genes regulated by Pou4f3 are likely to be essential for hair cell survival. We performed a subtractive hybridisation screen in an inner-ear-derived cell line to find genes with differential expression in response to changes in Pou4f3 levels. The screen identified the stress-granule-associated protein Caprin-1 as being downregulated by Pou4f3. We demonstrated that this regulation occurs through the direct interaction of Pou4f3 with binding sites in the Caprin-1 5' flanking sequence, and describe the expression pattern of Caprin-1 mRNA and protein in the cochlea. Moreover, we found Caprin-1-containing stress granules are induced in cochlear hair cells following aminoglycoside-induced damage. This is the first report of stress granule formation in mammalian hair cells and suggests that the formation of Caprin-1-containing stress granules is a key damage response to a clinically relevant ototoxic agent. Our results have implications for the understanding of aminoglycoside-induced hearing loss and provide further evidence that stress granule formation is a fundamental cellular stress response.
authors.affiliation: UCL Ear Institute, 332 Gray's Inn Road, London WC1X 8EE, UK.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Towers
authors.forename: John J
authors.initials: JJ
authors.lastname: Kelly
authors.forename: Richa
authors.initials: R
authors.lastname: Sud
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Gale
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Dawson
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology / Q000378:metabolism*; D003638:Deafness / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D050821:Transcription Factor Brn-3C / Q000235:genetics / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; C486565:Caprin1 protein, mouse; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C121290:Pou4f3 protein, mouse; D050821:Transcription Factor Brn-3C