Hair Cell Development in the Mammalian Cochlea

National Institute On Deafness And Other Communication Disorders

Investigators

Linked publications, trials & patents

Abstract

Auditory and vestibular function are dependent of the formation of a functional inner ear. While there are multiple components for both of these systems, this laboratory focuses on the development of the sensory epithelia, which contain mechanosensory hair cells and associated cells called supporting cells and on the innervation of those hair cells by neurons from the VIIIth (acousticovestibular) cranial nerve. All three of these cell types are derived from the otocyst, a placodal structure that forms adjacent to the hindbrain early in development. Identifying the factors that specify each of these cell types and then direct their assembly into functional units is a key goal of the Section on Developmental Neuroscience. During the previous year, different members of the laboratory have examined several different aspects of these developmental processes. Overall activity in the laboratory continued to be significantly affected by the COVID-mandated reduction in occupancy and two forced cullings of our animal colony because of COVID-related shortages in staffing. However, we were able to publish several collaborative studies and the results of a project examining the effects of concussive blast on auditory structure and function. As part of a collaboration with Dr. Karen Avrahams laboratory at Tel Aviv University we identified the first example of deafness in a human family as a result of mutations in the transcription factor ATOH1. Atoh1 has been known to be required for the development of hair cells in mice for over 20 years, but no examples of human deafness has been reported, most likely because complete deletion of Atoh1 leads to lethality. However, Dr. Avrahams lab was able to identify a family with congenital deafness as a result of a mutation in ATOH1. My laboratory demonstrated that the mutated form of ATOH1 is still functional but that the mutation leads to increased protein stability. Since down-regulation of Atoh1 in mice has been shown to be important for hair cell survival, we hypothesized that the increased stability is actually detrimental to hair cells, leading to deafness. As part of our collaboration, we are in the process of generating a mouse carrying the humanized Atoh1 mutation to continue this study. We also published the results of a long term project examining the effects of concussive blast on auditory and vestibular function. Loss of hearing, tinnitus and vertigo are commonly reported in veterans returning from active duty in Iraq or Afghanistan. To determine the biological basis for these complaints, we collaborated with the laboratory of Dr. Joseph Long at WRAIR to expose mice to concussive blast and then study auditory and vestibular changes over time. Our results demonstrated that hearing loss in response to concussive blast includes several different types of pathologies including loss of hair cells, loss of synapses and damage to the tympanic membrane. Some of these defects recover over time while others appear to be permanent. In addition, the vestibular system, which plays a key role in vertigo, appears to be undamaged following blast, suggesting that the vertigo suffered by service men and women may represent damage to the central, rather than peripheral, system. In other collaborations, we identified novel long non-coding RNAs that are expressed in the mouse cochlea and we continued to work on the application of single cell RNA sequencing to the understanding of sensory system development.