A model for generating differences in microtubules between axonal branches depending on the distance from terminals

Area of Science:

• Neuroscience
• Cell Biology
• Biophysics

Background:

• Axonal arbor remodeling involves differential regulation of branch growth and retraction.
• Microtubule (MT) turnover differences are implicated in selective branch regulation, but the underlying cellular mechanisms remain unclear.
• Slower MT turnover in longer axonal branches suggests length-dependent feedback regulation.

Purpose of the Study:

• To clarify the cellular system by which neurons generate differences in microtubule dynamics between axonal branches.
• To model microtubule (MT) lifetime in axonal terminal branches and investigate feedback regulation.
• To understand how axonal arbor geometry influences MT regulation.

Main Methods:

• Developed a computational model of MT lifetime in axonal terminal branches, adapting a length-dependent model.
• Simulated MT dynamics with constant parameters across the arbor.
• Used expansion microscopy and nocodazole treatment in primary neurons to analyze MT turnover indicators (detyrosination/tyrosination).

Main Results:

• The model predicted that MT lifetime differences between neighboring branches arise from distance-dependent feedback.
• MT destabilization reduced inter-branch MT lifetime differences.
• MT lifetime differences were observed even before microtubules entered branch points.
• Experimental data showed reduced detyrosination/tyrosination differences upon nocodazole treatment, correlating with MT turnover.
• Expansion microscopy revealed pre-branch point MT modification differences.

Conclusions:

• The developed model successfully recapitulates observed inter-branch MT turnover differences.
• A feedback mechanism for MT regulation dependent on axonal arbor geometry is proposed.
• This study provides insights into the cellular basis of differential MT regulation within neuronal arbors.