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bioRxiv · 10.1101/2022.07.12.499810

NudC regulated Lis1 stability is essential for maintenance of dynamic microtubule ends in the axon terminal

Kawano, D.·Pinter, K.·Chlebowski, M.·Petralia, R. S.·Wang, Y.-X.·Nechiporuk, A.·Drerup, C.
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Abstract

Axon terminal structure is critical for neuronal function. This cellular compartment houses synaptic terminals and is a site of high metabolic and functional demand. Axon terminals are also the site of a change in microtubule structure within the neuron. Microtubule stability is decreased relative to the axon shaft due to an enrichment of microtubule plus ends and increase in microtubule dynamics. These dynamic microtubule plus ends have many functions including serving as a docking site for the microtubule motor protein complex Cytoplasmic dynein. Here, we report an unexplored function of the dynein motor in axon terminals: regulation of microtubule stability. Using a forward genetic screen, we identified a mutant with abnormal axon terminal structure due to a loss of function mutation in the dynein interacting protein NudC. We show that the primary function of NudC in the axon terminal is as a chaperone for the protein Lis1. Loss of NudC results in decreased Lis1 protein in this neuronal compartment. Decreased Lis1 in nudc mutants causes dynein/dynactin accumulation and increased microtubule stability in axon terminals. Microtubules in the proximal axon are unaffected. Abnormal microtubule stability and structure can be suppressed by pharmacologically inhibiting dynein, implicating excess dynein motor activity as causal in the enhanced axon terminal microtubule stability. Together, our data support a model in which local NudC-Lis1 modulation of dynein motor activity is critical for regulation of microtubule stability in the axon terminal.

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Kawano, D., Pinter, K., Chlebowski, M., Petralia, R. S., Wang, Y.-X., Nechiporuk, A., Drerup, C.. 2022-07-13. NudC regulated Lis1 stability is essential for maintenance of dynamic microtubule ends in the axon terminal. https://doi.org/10.1101/2022.07.12.499810

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