ORCID ID

0000-0001-8385-608X

Publication Date

2021-09-01

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Neurobiology

First Thesis Advisor

Alexandra Byrne

Keywords

axon, regeneration, degeneration, Sarm1, tir-1, C. elegans, neurobiology

Abstract

The inability to repair axonal damage is a feature of neurological impairment after injury and in neurodegenerative diseases. Axonal repair after injury depends in part on intrinsic factors. Several genes cell-autonomously regulate both axon regeneration and degeneration in response to injury. Recently, Sarm1 has emerged as a key regulator of neurodegeneration. Whether Sarm1 plays a role in axon regeneration is unknown. In this thesis, I identified a role for the C. elegans homolog of Sarm1, tir-1, as a negative regulator of axon regeneration.

Investigating the genes which regulate axon regeneration and degeneration has been hindered by technical difficulties in visualizing and manipulating both of these processes in vivo simultaneously. To circumvent this challenge, I developed a new model of axon injury, where both axon regeneration and degeneration can be monitored in vivo with single neuron resolution in C. elegans. I found that the C. elegans homolog of Sarm1, tir-1, strongly inhibits axon regeneration in response to injury. I found that TIR-1 functions cell-intrinsically and that its subcellular localization is dynamically regulated in response to injury. To regulate both axon regeneration and degeneration after injury, I found that TIR-1 function is determined by interaction with two distinct genetic pathways. Together, this work reveals a novel role for tir-1/Sarm1 in axon regeneration, increases our understanding of the injury response, provides new avenues of investigation for studies of TIR-1/SARM1, and inspires candidate approaches to repair the injured nervous system.

DOI

10.13028/nryq-6g69

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Wednesday, September 13, 2023

Share

COinS