Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner
| Autor: | Suzan L. Harris, Martin Schwander, Anthony W. Peng, Marcin Kazmierczak, Marc Lenoir, Prahar Shah, Jean-Luc Puel, Piotr Kazmierczak, Santos J. Franco |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Hearing loss Hearing Loss Sensorineural Auditory neuropathy Biology Mechanotransduction Cellular Cell Line Stereocilia 03 medical and health sciences Mice Auditory neuropathy spectrum disorder Hearing Hair Cells Auditory medicine otorhinolaryngologic diseases Missense mutation Animals Inner ear Mechanotransduction Research Articles integumentary system General Neuroscience Microfilament Proteins Proteins medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cell culture Mutation Hair cell sense organs medicine.symptom Neuroscience |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 37(13) |
| ISSN: | 1529-2401 |
| Popis: | Mutations in thePejvakin(PJVK) gene are thought to cause auditory neuropathy and hearing loss of cochlear origin by affecting noise-induced peroxisome proliferation in auditory hair cells and neurons. Here we demonstrate that loss of pejvakin in hair cells, but not in neurons, causes profound hearing loss and outer hair cell degeneration in mice. Pejvakin binds to and colocalizes with the rootlet component TRIOBP at the base of stereocilia in injectoporated hair cells, a pattern that is disrupted by deafness-associatedPJVKmutations. Hair cells of pejvakin-deficient mice develop normal rootlets, but hair bundle morphology and mechanotransduction are affected before the onset of hearing. Some mechanotransducing shorter row stereocilia are missing, whereas the remaining ones exhibit overextended tips and a greater variability in height and width. Unlike previous studies ofPjvkalleles with neuronal dysfunction, our findings reveal a cell-autonomous role of pejvakin in maintaining stereocilia architecture that is critical for hair cell function.SIGNIFICANCE STATEMENTTwo missense mutations in thePejvakin(PJVKorDFNB59) gene were first identified in patients with audiological hallmarks of auditory neuropathy spectrum disorder, whereas all otherPJVKalleles cause hearing loss of cochlear origin. These findings suggest that complex pathogenetic mechanisms underlie human deafness DFNB59. In contrast to recent studies, we demonstrate that pejvakin in auditory neurons is not essential for normal hearing in mice. Moreover, pejvakin localizes to stereociliary rootlets in hair cells and is required for stereocilia maintenance and mechanosensory function of the hair bundle. Delineating the site of the lesion and the mechanisms underlying DFNB59 will allow clinicians to predict the efficacy of different therapeutic approaches, such as determining compatibility for cochlear implants. |
| Databáze: | OpenAIRE |
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