TY - JOUR
T1 - NudC regulated Lis1 stability is essential for the maintenance of dynamic microtubule ends in axon terminals
AU - Kawano, Dane
AU - Pinter, Katherine
AU - Chlebowski, Madison
AU - Petralia, Ronald S.
AU - Wang, Ya Xian
AU - Nechiporuk, Alex V.
AU - Drerup, Catherine M.
N1 - Funding Information:
Funding for this work was provided by the Provost and the Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin-Madison with funding from the Wisconsin Alumni Research Foundation (to C.M.D.), the NINDS ( NS111419 to A.V.N), and the NIH Intramural Research Program Grants from the NICHD ( 1ZIAHD008964-02 to C.M.D.) and the NIDCD ( DC000081 to R.S.P. and Y.-X. W.). We want to thank A. Mandal, K. Klier, S. Wisner, H-T. C. Wong, C. Stein, A. Lang, and D. Mai for their thoughtful comments on this work. We would like to also acknowledge E.P. Louise for his suggestion to try the dynein inhibition experiment. PatroninCC and LC3 constructs were acquired from Addgene.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/10/21
Y1 - 2022/10/21
N2 - In the axon terminal, microtubule stability is decreased relative to the axon shaft. The dynamic microtubule plus ends found in the axon terminal have many functions, including serving as a docking site for the Cytoplasmic dynein motor. Here, we report an unexplored function of dynein in microtubule regulation in axon terminals: regulation of microtubule stability. Using a forward genetic screen, we identified a mutant with an abnormal axon terminal structure owing to a loss of function mutation in NudC. We show that, in the axon terminal, NudC is a chaperone for the protein Lis1. Decreased Lis1 in nudc axon terminals causes dynein/dynactin accumulation and increased microtubule stability. Microtubule dynamics can be restored by pharmacologically inhibiting dynein, implicating excess dynein motor function in microtubule stabilization. Together, our data support a model in which local NudC-Lis1 modulation of the dynein motor is critical for the regulation of microtubule stability in the axon terminal.
AB - In the axon terminal, microtubule stability is decreased relative to the axon shaft. The dynamic microtubule plus ends found in the axon terminal have many functions, including serving as a docking site for the Cytoplasmic dynein motor. Here, we report an unexplored function of dynein in microtubule regulation in axon terminals: regulation of microtubule stability. Using a forward genetic screen, we identified a mutant with an abnormal axon terminal structure owing to a loss of function mutation in NudC. We show that, in the axon terminal, NudC is a chaperone for the protein Lis1. Decreased Lis1 in nudc axon terminals causes dynein/dynactin accumulation and increased microtubule stability. Microtubule dynamics can be restored by pharmacologically inhibiting dynein, implicating excess dynein motor function in microtubule stabilization. Together, our data support a model in which local NudC-Lis1 modulation of the dynein motor is critical for the regulation of microtubule stability in the axon terminal.
KW - Molecular neuroscience
KW - developmental neuroscience
KW - functional aspects of cell biology
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U2 - 10.1016/j.isci.2022.105072
DO - 10.1016/j.isci.2022.105072
M3 - Article
AN - SCOPUS:85138116209
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 10
M1 - 105072
ER -