Hair cell overexpression of Islet1 reduces age-related and noise-induced hearing loss.
Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells. Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic of the age-related hearing loss (ARHL) in the background strain (C57BL/6J). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates. Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure.
Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts 02115, Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
Mingqian
M
Huang
Albena
A
Kantardzhieva
Deborah
D
Scheffer
M Charles
MC
Liberman
Zheng-Yi
ZY
Chen
D000161:Acoustic Stimulation; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D003051:Cochlea / Q000473:pathology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017084:Otoacoustic Emissions, Spontaneous; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D050821:Transcription Factor Brn-3C / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; C121290:Pou4f3 protein, mouse; D012333:RNA, Messenger; D050821:Transcription Factor Brn-3C; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D049452:Green Fluorescent Proteins