Cargando…
Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss
The mammalian cochlea is an exceptionally well-organized epithelium composed of hair cells, supporting cells, and innervating neurons. Loss or defects in any of these cell types, particularly the specialized sensory hair cells, leads to deafness. The Notch pathway is known to play a critical role in...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674855/ https://www.ncbi.nlm.nih.gov/pubmed/36400760 http://dx.doi.org/10.1038/s41419-022-05380-w |
_version_ | 1784833239579361280 |
---|---|
author | Gilels, Felicia A. Wang, Jun Bullen, Anwen White, Patricia M. Kiernan, Amy E. |
author_facet | Gilels, Felicia A. Wang, Jun Bullen, Anwen White, Patricia M. Kiernan, Amy E. |
author_sort | Gilels, Felicia A. |
collection | PubMed |
description | The mammalian cochlea is an exceptionally well-organized epithelium composed of hair cells, supporting cells, and innervating neurons. Loss or defects in any of these cell types, particularly the specialized sensory hair cells, leads to deafness. The Notch pathway is known to play a critical role in the decision to become either a hair cell or a supporting cell during embryogenesis; however, little is known about how Notch functions later during cochlear maturation. Uniquely amongst Notch ligands, Jagged1 (JAG1) is localized to supporting cells during cell fate acquisition and continues to be expressed into adulthood. Here, we demonstrate that JAG1 in maturing cochlear supporting cells is essential for normal cochlear function. Specifically, we show that deletion of JAG1 during cochlear maturation disrupts the inner hair cell pathway and leads to a type of deafness clinically similar to auditory neuropathy. Common pathologies associated with disruptions in inner hair cell function, including loss of hair cells, synapses, or auditory neurons, were not observed in JAG1 mutant cochleae. Instead, RNA-seq analysis of JAG1-deficient cochleae identified dysregulation of the Rho GTPase pathway, known to be involved in stereocilia development and maintenance. Interestingly, the overexpression of one of the altered genes, Diaph3, is responsible for autosomal dominant auditory neuropathy-1 (AUNA1) in humans and mice, and is associated with defects in the inner hair cell stereocilia. Strikingly, ultrastructural analyses of JAG1-deleted cochleae revealed stereocilia defects in inner hair cells, including fused and elongated bundles, that were similar to those stereocilia defects reported in AUNA1 mice. Taken together, these data indicate a novel role for Notch signaling in normal hearing development through maintaining stereocilia integrity of the inner hair cells during cochlear maturation. |
format | Online Article Text |
id | pubmed-9674855 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96748552022-11-20 Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss Gilels, Felicia A. Wang, Jun Bullen, Anwen White, Patricia M. Kiernan, Amy E. Cell Death Dis Article The mammalian cochlea is an exceptionally well-organized epithelium composed of hair cells, supporting cells, and innervating neurons. Loss or defects in any of these cell types, particularly the specialized sensory hair cells, leads to deafness. The Notch pathway is known to play a critical role in the decision to become either a hair cell or a supporting cell during embryogenesis; however, little is known about how Notch functions later during cochlear maturation. Uniquely amongst Notch ligands, Jagged1 (JAG1) is localized to supporting cells during cell fate acquisition and continues to be expressed into adulthood. Here, we demonstrate that JAG1 in maturing cochlear supporting cells is essential for normal cochlear function. Specifically, we show that deletion of JAG1 during cochlear maturation disrupts the inner hair cell pathway and leads to a type of deafness clinically similar to auditory neuropathy. Common pathologies associated with disruptions in inner hair cell function, including loss of hair cells, synapses, or auditory neurons, were not observed in JAG1 mutant cochleae. Instead, RNA-seq analysis of JAG1-deficient cochleae identified dysregulation of the Rho GTPase pathway, known to be involved in stereocilia development and maintenance. Interestingly, the overexpression of one of the altered genes, Diaph3, is responsible for autosomal dominant auditory neuropathy-1 (AUNA1) in humans and mice, and is associated with defects in the inner hair cell stereocilia. Strikingly, ultrastructural analyses of JAG1-deleted cochleae revealed stereocilia defects in inner hair cells, including fused and elongated bundles, that were similar to those stereocilia defects reported in AUNA1 mice. Taken together, these data indicate a novel role for Notch signaling in normal hearing development through maintaining stereocilia integrity of the inner hair cells during cochlear maturation. Nature Publishing Group UK 2022-11-18 /pmc/articles/PMC9674855/ /pubmed/36400760 http://dx.doi.org/10.1038/s41419-022-05380-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Gilels, Felicia A. Wang, Jun Bullen, Anwen White, Patricia M. Kiernan, Amy E. Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
title | Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
title_full | Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
title_fullStr | Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
title_full_unstemmed | Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
title_short | Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
title_sort | deletion of the notch ligand jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674855/ https://www.ncbi.nlm.nih.gov/pubmed/36400760 http://dx.doi.org/10.1038/s41419-022-05380-w |
work_keys_str_mv | AT gilelsfeliciaa deletionofthenotchligandjagged1duringcochlearmaturationleadstoinnerhaircelldefectsandhearingloss AT wangjun deletionofthenotchligandjagged1duringcochlearmaturationleadstoinnerhaircelldefectsandhearingloss AT bullenanwen deletionofthenotchligandjagged1duringcochlearmaturationleadstoinnerhaircelldefectsandhearingloss AT whitepatriciam deletionofthenotchligandjagged1duringcochlearmaturationleadstoinnerhaircelldefectsandhearingloss AT kiernanamye deletionofthenotchligandjagged1duringcochlearmaturationleadstoinnerhaircelldefectsandhearingloss |