Student Theses and Dissertations

Date of Award

2026

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Thesis Advisor

A. James Hudspeth

Keywords

hair cell, collagen XVIII, axon guidance, Schwann cell, zebrafish, lateral line

Abstract

Loss of hearing is a prevalent sensory pathology in the United States and worldwide. A significant proportion of deafness is attributed to sensorineural hearing loss, which often involves damage and retraction of the nerve fibers that relay auditory information between the mechanosensitive hair cells of the inner ear and the brain. The restoration of physiologic hearing would require the regeneration of nerve fibers back into the sensory epithelium of the cochlea, followed by the reinnervation of appropriate hair cell targets. Nerve regeneration studies in humans and other mammalian models are lacking due to the limited accessibility of the inner ear. Alternatively, the zebrafish lateral line, a mechanosensory organ system unique to fishes and amphibians that detects external water flow, offers a simple and accessible model for studying the mechanisms of axon pathfinding and target selection. The posterior portion of the lateral line is composed of superficial sensory hair cells, genetically and functionally similar to hair cells of the inner ear, clustered into organs called neuromasts that are scattered across the trunk and tail. The posterior lateral line nerve spans the entire length of the fish, relaying information to and from neuromasts located across the body surface. Regeneration of the posterior lateral line nerve of the zebrafish and subsequent reinnervation of hair cells within neuromasts is both rapid and precise. My thesis work focuses on identifying the factors both internal and external to the regenerating fibers of the lesioned nerve that guide severed axons back to their hair cell targets. I first employed a fluorescent labeling strategy to differentially label subgroups of neurons in the posterior lateral line nerve, and their innervation pattern before and after nerve lesion. I found that there is plasticity in the selection of neuromasts during nerve regeneration, which suggests that the path taken by axon growth cones is not hardwired based on the original chronotopy of the neural circuit and can instead be biased by cues in the extracellular environment. Next, I profiled denervated and innervated hair cells through bulk RNA sequencing to determine candidate genes expressed by the ultimate targets of innervation that may be guiding axons to their destination. I confirmed that denervation induces a change in the transcriptome of hair cells. One of the genes upregulated in the denervated hair cells, which codes for a non-fibrillar type of collagen, is also selectively expressed by Schwann cells that lie at branching points of the nerve. These branching points coincide with gaps in the extracellular matrix that permit the entry of defasciculated axon fibers into the epidermis in which neuromasts reside. Selective mutation of this collagen gene altered the shape and structure of the posterior lateral line nerve and also resulted in aberrant branching following nerve lesion. These results indicate that this atypical collagen, Collagen XVIII, is crucial for maintaining the spatial fidelity of axon navigation. Together, this body of work provides evidence towards multiple cellular and molecular interactions that guide posterior lateral line nerve regeneration and may provide insight into promoting the reinnervation of otherwise permanently damaged sensory tissue.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy

License and Reuse Information

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.

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