Dissertation
Regulation of axonal microtubule organization by microtubule motors and static crosslinkers
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000856
Abstract
Previous studies have shown that cytoplasmic dynein is the principal molecular motor protein responsible for polarity sorting axonal microtubules, and that it does so by sliding plus-end-out microtubules into and down the axon while sliding minus-end-out microtubule back into the cell body. However, most of the microtubule mass in the axon is relatively stationary, with sliding limited mainly to short microtubules. Moreover, the trajectory of these sliding microtubules is often accompanied by tugs in the other direction and even infrequent reversals. Computational modeling suggests two novel contributors to explain these results: static microtubule crosslinkers that limit sliding mostly to short microtubules, and an opposing motor that creates the observed tugs and reversals. Insufficient crosslinking and/or too much activity of the opposing motor would obstruct normal polarity sorting and lead to microtubule polarity flaws. Consistent with these predictions, experimental depletion from primary cultures of rat neurons of TRIM46 or PRC1, two static microtubule crosslinkers with very different properties, results in greater mobility within the axonal microtubule array. Interestingly, microtubule polarity flaws arise in the axons of hippocampal neurons but not sympathetic neurons, possibly due to greater activity of the opposing motor in hippocampal neurons. Consistent with that motor being kinesin-1, a pharmacologic shift of its forces toward microtubule sliding creates microtubule polarity flaws and aberrant sliding of even long microtubules. In addition to validating features of the polarity sorting model, these observations highlight new targets that may be implicated in disease states presenting with aberrant microtubule organization.
Metrics
40 File views/ downloads
34 Record Views
Details
- Title
- Regulation of axonal microtubule organization by microtubule motors and static crosslinkers
- Creators
- Ankita Patil
- Contributors
- Timothy J. Cunningham (Advisor)Peter W. Baas (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- viii, 93 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991015588362504721