Determining the Role of Gata3 in a Sub-Population of Vestibular Hair Cells

Date of Award

4-2022

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Jeremy Duncan, Ph.D.

Second Advisor

Christine Byrd-Jacobs, Ph.D.

Third Advisor

John Spitsbergen, Ph.D.

Fourth Advisor

Yong Li, M.D., Ph.D.

Keywords

Cochlea, Gata3, hair cells, HDR syndrome, utricle

Abstract

The inner ear can be divided based on two functions: hearing and balance. The hearing organ is called the cochlea, while the organs responsible for balance are called the vestibular system. One of these vestibular organs, the utricle, is positioned horizontally in the body and relatively parallel to the ground, resulting in sensitive detection of both sideways, and forward and backward acceleration. One major question in the field of otolaryngology focuses on the unique differences between these organs and the evolutionary importance of their similarities. One particular gene of interest called Gata3 is initially expressed highly in the cochlea and utricle, but its dynamic expression is down-regulated at key developmental time points associated with sensory cell fate and specification. Both too little and too high levels of Gata3 have been associated with human disorder Hypoparathyroidism, Deafness, and Renal dysplasia (HDR) syndrome. Therefore, manipulation of Gata3 has been suggested as a potential therapeutic target.

This thesis will first review the development of the utricle and cochlea. I will then summarize the current knowledge of Gata3 in the inner ear, its known expression patterns and role in sensory cell development, and its connection to HDR Syndrome. I examine the role of Gata3 in a model of age-related hearing loss in the cochlea. Since this data supported previous studies that suggest Gata3 can make sensory regeneration more efficient, I then determined that forced Gata3 expression in existing sensory cells in the cochlea was not detrimental to those cells. This phenomenon further supports that manipulation of Gata3 in a cochlea in any stage of deafness could be used to guide future treatment. Previously RNA-sequencing data has suggested that levels of Gata3 could contribute to different sensory cell populations in the utricle specifically, and qPCR data from my project in the cochlea suggested that the vestibular system is more susceptible to manipulation overall.

Therefore, I then examined the over-expression and loss of Gata3 within sensory cell populations in the utricle using two cre driver lines (Atoh1-cre expressed in all mechanosensory hair cells (HCs), and Fgf8-cre expressed in a sub-population of mechanosensory HCs called Type I HCs). Loss of Gata3 in all HCs results a shift from Type I HCs to Type II HCs. Loss of Gata3 in only the Type I HCs results in a morphologically smaller utricle and fewer, smaller HCs overall which is maintained postnatally. Furthermore, both loss and gain of Gata3 in the Type I HCs changes the complexity of synapses in unique functional regions of the utricle. Therefore, my data demonstrates that very specific levels of Gata3 are required for correct sensory cell development, maintenance, and even innervation patterns of those sensory cells. My contribution to the field adds to previous knowledge about Gata3 and the necessity of Gata3 for function of specific cell types. Additionally, my research supports a growing amount of evidence that Gata3, like other transcription factors in the inner ear, should be investigated as a future therapeutic option for hearing loss or vestibular disorders.

Access Setting

Dissertation-Open Access

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