Abstract
Proper regulation of microtubule (MT) dynamics is vital for essential cellular processes and many neuronal activities, including axonal transport and synaptic growth and remodeling. Here we demonstrate that Mask negatively regulates MT stability and maintains a balanced MT length and architecture in both fly larval muscles and motor neurons. In larval muscles, loss of mask increases MT length, and altering mask genetically modifies the Tau-induced MT fragmentation. In motor neurons, loss of mask function reduces the number of End-Binding Protein 1 (EB1)-positive MT plus-ends in the axons and results in overexpansion of the presynaptic terminal at larval neuromuscular junctions (NMJ). mask shows strong genetic interaction with stathmin (stai), a neuronal modulator of MT dynamics, in regulation of axon transportation and synaptic terminal stability. The structure/function analysis on Mask suggests that Mask’s action in regulating MT stability does not depend on the nucleotide-binding function of its KH domain. Furthermore, through a proteomic approach, we found that Mask physically interacts with Jupiter, an MT stabilizing factor. The MT localization of Jupiter in the axons inversely correlates with Mask levels, suggesting that Mask may modulate MT stability by inhibiting the association of Jupiter to MTs.
Author Summary Microtubules (MT) are part of the cytoskeleton of the cells that provides essential structural basis for critical processes and functions of the cells. A complex factors are required to orchestrate the assembly and disassembly of MT. Here we identified Mask as a novel regulator for MT dynamics in fruit flies. Mask negatively regulates MT stability. It shows prominent interplay with two important modulators of MT, Tau and Stathmin (Stai), both genes are linked to human neurodegenerative disorders. These findings not only support the role of Mask as a novel microtubule regulator, but also provide foundation to explore future therapeutic strategies in mitigating deficit related to dysfunction of Tau and Stathmin. Our further analysis on Mask protein demonstrate that Mask can physically interacts with another MT stabilizing factor named Jupiter. Jupiter can bind to MT, but its localization to the MTs in the axons is negatively affected by Mask, implying a possible underlying mechanism that Mask may modulate MT stability by inhibiting the association of Jupiter to MTs.
Competing Interest Statement
The authors have declared no competing interest.