Date of Award
Fall 12-2-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
First Advisor
Murray Blackmore
Second Advisor
Alex Savtchouk
Third Advisor
Jennifer Evans
Abstract
Spinal cord injury (SCI) affects millions of people worldwide. Damage to the spinal cord disrupts the long-distance axon tracts of central nervous system (CNS) neurons. These axons fail to regenerate, leading to permanent dysfunction. Past work has shown that CNS neurons lose the capacity to elongate their axons as they mature. Conversely, after injury, embryonic and peripheral nervous system (PNS) neurons can elongate axons towards target cells, driven by the growth cone at the growing tip of the axon. Previous research has identified transcription factor (TF) families, such as the SoxC family, that contribute to embryonic and peripheral neurons’ high capacity for axon elongation. Therefore, this dissertation investigates the hypothesis that axon elongation is regulated by a biologically conserved gene program characterized by the activation of growth-related processes enriched for growth cone–associated proteins and the concurrent suppression of synaptic processes, a pattern shared between developing and regenerating neurons. This conserved program underlies the intrinsic capacity of neurons to initiate and sustain axonal elongation, regardless of the context. I predicted that TFs which regulate both developmental and regenerative instances of axon elongation could activate this conserved gene program in adult CNS neurons, enhancing their intrinsic capacity for axon elongation, with the overarching goal of restoring regenerative capacity, rebuilding functional circuits, and returning functions to individuals with a SCI. In the present studies, I employ single-nucleus RNA sequencing to demonstrate that thousands of genes change through CNS maturation. I then go on to showcase that these genes which change in developing CNS neurons, during PNS regeneration, and which are relevant in growth cone function share a gene program enriched for activation of translation, transport, and cytoskeletal organization, Lastly, I demonstrate that the combination of Sox11 and Klf6 activates this conserved gene program for axon elongation in the CNS, enhancing neurons intrinsic capacity for axon elongation. Collectively, these studies provide novel insight into conserved gene programs for axon elongation and potential pro-regenerative interventions for SCI. Extending beyond this dissertation, these studies provide a framework that subsequent regeneration biologists can leverage to enhance intrinsic growth capacity in other neurodegenerative diseases.
Comments
Doctor of Philosophy (PhD)