Investigation of Notch Signaling during Spontaneous Regeneration of Cochlear Hair Cells
Abstract
Hearing loss and tinnitus commonly occur after exposure to intense or prolonged levels of loud noise which are inherent to military settings. These noise exposures damage and kill sensory hair cells (HCs) found in the cochlea of the inner ear, resulting in permanent hearing loss and tinnitus. Regeneration of auditory HCs and recovery of hearing function naturally occurs in non-mammalian vertebrates. In contrast, auditory HCs are not replaced after damage in humans and other mature mammals. However, we have recently discovered that the neonatal mouse cochlea is capable of spontaneous HC regeneration. Understanding the molecular mechanism that allows spontaneous HC regeneration to occur in neonatal mice is the first step to stimulating successful HC regeneration in adults and translating these findings to humans who suffer from hearing loss. Our central hypothesis is that following HC damage in the neonatal mouse cochlea, Notch signaling is decreased which causes supporting cells (SCs) to change cell fate and become HCs. We are also investigating the relationship between individual Notch ligands and target genes in the undamaged, neonatal cochlea to understand which ligands control supporting cell to HC conversion. Our data show changes in Notch signaling following HC damage in two SC subtypes (pillar cells and Deiters' cells), but not in other subtypes. We also demonstrate that when Notch signaling is increased in SCs, HC regeneration is reduced by 92%. Therefore we conclude that reduced Notch signaling is required for spontaneous HC regeneration to occur. We also investigated deletion of individual Notch ligands from HCs or SCs and found loss of specific SC subtypes after deletion of one of more Notch ligands. Together, these data suggest that the Notch signaling pathway is a complex network of signaling from different ligands that regulate HC and SC fate in the neonatal cochlea.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2019
- Accession Number
- AD1095151
Entities
People
- Brandon C Cox
- Chantz Pinder
- Kaley A. Graves
- Luyi Zhou
- Melissa M. Mcgovern
- Michelle R. Randle
- Yuanzhao L. Darcy
Organizations
- Southern Illinois University School of Medicine