Author ORCID Identifier

https://orcid.org/0009-0006-9361-6673

Date of Award

2026

Document Type

Thesis (Ph.D.)

Department or Program

Integrative Neuroscience

First Advisor

Jennifer Hong

Abstract

Peripheral neuropathy is a wide-spread, growing public health issue, with poor clinical outcomes and a lack of available regenerative treatments. A major limitation to the development of novel therapies is poor understanding of the molecular mechanisms driving regeneration in peripheral neurons. One factor of interest in peripheral neuropathy is the tumor-suppressor phosphatase Pten. Pten knockout has been previously shown to promote axon regeneration in a variety of neuronal subtypes, and to promote functional recovery in animal models of peripheral nerve injury. One of Pten's downstream targets is the microtubule cytoskeleton, and past work from our lab has found Pten-KO accelerates microtubule polymerization rates in the axonal growthcone. However, Pten has an extremely broad range of downstream effectors, and it remains unclear whether Pten-KO drives growth via the microtubule cytoskeleton or through an independent mechanism. Here, we isolate the cytoskeletal effects of Pten through a series of genetic manipulations, and find that Pten-KO appears to drive distal axonal elongation in peripheral sensory neurons via the microtubule cytoskeleton. We also show evidence for differential genetic regulation of microtubule dynamics across subaxonal compartments. Next, we extend these findings to a mouse model of diabetic neuropathy, the leading cause of peripheral neuropathy in the U.S. We build on previous studies showing that Pten is upregulated in diabetic neurons, and find that microtubule polymerization is suppressed in the growthcones of diabetic neurons. Interestingly, we find that Pten knockout has no effect on the microtubule cytoskeleton in these neurons, even though it still increases cellular-level growth. Our results suggest that diabetes impacts the microtubule cytoskeleton, which could contribute to the inhibited regeneration seen in diabetic neuropathy, via a Pten-independent mechanism. We also show that Pten-KO drives neuronal growth in diabetic neurons via a MT-independent mechanism. Overall, our results further elucidate the effects of Pten on the MT cytoskeleton in peripheral neurons, and highlight the MT cytoskeleton as a relevant, promising clinical target for the development of regenerative therapies in diabetic neuropathy.

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Available for download on Friday, October 09, 2026

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