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Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice

A knockin (KI) mouse expressing mutated prestin (V499G/Y501H) (499 prestin) was created to study cochlear amplification. Recordings from isolated outer hair cells (OHC) in this mutant showed vastly reduced electromotility and, as a consequence, reduced hearing sensitivity. Although 499 prestin OHCs...

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Autores principales: Cheatham, Mary Ann, Edge, Roxanne M., Homma, Kazuaki, Leserman, Emily L., Dallos, Peter, Zheng, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684303/
https://www.ncbi.nlm.nih.gov/pubmed/26682723
http://dx.doi.org/10.1371/journal.pone.0145428
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author Cheatham, Mary Ann
Edge, Roxanne M.
Homma, Kazuaki
Leserman, Emily L.
Dallos, Peter
Zheng, Jing
author_facet Cheatham, Mary Ann
Edge, Roxanne M.
Homma, Kazuaki
Leserman, Emily L.
Dallos, Peter
Zheng, Jing
author_sort Cheatham, Mary Ann
collection PubMed
description A knockin (KI) mouse expressing mutated prestin (V499G/Y501H) (499 prestin) was created to study cochlear amplification. Recordings from isolated outer hair cells (OHC) in this mutant showed vastly reduced electromotility and, as a consequence, reduced hearing sensitivity. Although 499 prestin OHCs were normal in stiffness and longer than OHCs lacking prestin, accelerated OHC death was unexpectedly observed relative to that documented in prestin knockout (KO) mice. These observations imply an additional role of prestin in OHC maintenance besides its known requirement for mammalian cochlear amplification. In order to gain mechanistic insights into prestin-associated OHC loss, we implemented several interventions to improve survival. First, 499 prestin KI’s were backcrossed to Bak KO mice, which lack the mitochondrial pro-apoptotic gene Bak. Because oxidative stress is implicated in OHC death, another group of 499 prestin KI mice was fed the antioxidant diet, Protandim. 499 KI mice were also backcrossed onto the FVB murine strain, which retains excellent high-frequency hearing well into adulthood, to reduce the compounding effect of age-related hearing loss associated with the original 499 prestin KIs. Finally, a compound heterozygous (chet) mouse expressing one copy of 499 prestin and one copy of KO prestin was also created to reduce quantities of 499 prestin protein. Results show reduction in OHC death in chets, and in 499 prestin KIs on the FVB background, but only a slight improvement in OHC survival for mice receiving Protandim. We also report that improved OHC survival in 499 prestin KIs had little effect on hearing phenotype, reaffirming the original contention about the essential role of prestin’s motor function in cochlear amplification.
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spelling pubmed-46843032015-12-31 Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice Cheatham, Mary Ann Edge, Roxanne M. Homma, Kazuaki Leserman, Emily L. Dallos, Peter Zheng, Jing PLoS One Research Article A knockin (KI) mouse expressing mutated prestin (V499G/Y501H) (499 prestin) was created to study cochlear amplification. Recordings from isolated outer hair cells (OHC) in this mutant showed vastly reduced electromotility and, as a consequence, reduced hearing sensitivity. Although 499 prestin OHCs were normal in stiffness and longer than OHCs lacking prestin, accelerated OHC death was unexpectedly observed relative to that documented in prestin knockout (KO) mice. These observations imply an additional role of prestin in OHC maintenance besides its known requirement for mammalian cochlear amplification. In order to gain mechanistic insights into prestin-associated OHC loss, we implemented several interventions to improve survival. First, 499 prestin KI’s were backcrossed to Bak KO mice, which lack the mitochondrial pro-apoptotic gene Bak. Because oxidative stress is implicated in OHC death, another group of 499 prestin KI mice was fed the antioxidant diet, Protandim. 499 KI mice were also backcrossed onto the FVB murine strain, which retains excellent high-frequency hearing well into adulthood, to reduce the compounding effect of age-related hearing loss associated with the original 499 prestin KIs. Finally, a compound heterozygous (chet) mouse expressing one copy of 499 prestin and one copy of KO prestin was also created to reduce quantities of 499 prestin protein. Results show reduction in OHC death in chets, and in 499 prestin KIs on the FVB background, but only a slight improvement in OHC survival for mice receiving Protandim. We also report that improved OHC survival in 499 prestin KIs had little effect on hearing phenotype, reaffirming the original contention about the essential role of prestin’s motor function in cochlear amplification. Public Library of Science 2015-12-18 /pmc/articles/PMC4684303/ /pubmed/26682723 http://dx.doi.org/10.1371/journal.pone.0145428 Text en © 2015 Cheatham et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cheatham, Mary Ann
Edge, Roxanne M.
Homma, Kazuaki
Leserman, Emily L.
Dallos, Peter
Zheng, Jing
Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice
title Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice
title_full Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice
title_fullStr Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice
title_full_unstemmed Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice
title_short Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in Prestin (V499G/Y501H) Knockin Mice
title_sort prestin-dependence of outer hair cell survival and partial rescue of outer hair cell loss in prestin (v499g/y501h) knockin mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684303/
https://www.ncbi.nlm.nih.gov/pubmed/26682723
http://dx.doi.org/10.1371/journal.pone.0145428
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