Dynamic balance between vesicle transport and microtubule growth enables neurite growth

Whole cell responses are complex because they involve many subcellular processes (SCPs) that need to function in a coordinated manner. Detailed understanding of how different SCPs function in a coordinated manner to produce an integrated whole cell response requires mathematical models that capture the dynamics of the individual SCPs as well as the interrelationship between the dynamics of multiple SCPs. We studied neurite outgrowth the initial process by which neurons develop axons and dendrites to understand how balance between subcellular processes is essential for the growth of neurite at experimentally observed rates. Neurite outgrowth involves two types of SCPs: membrane vesicle production/transport/fusion at the growing tip that adds membrane to the growth cone and neurite shaft, and microtubule growth and stabilization that regulates extension of the neurite shaft. Each type of SCP is composed of multiple lower level SCPs. We developed multicompartment ordinary differential equation based models to simulate how coordinated activity of these types of SCPs leads to neurite outgrowth. We utilized imaging experiments of primary cortical neurons to obtain velocities of neurite outgrowth and used these growth velocities as overall constraints with the starting postulate that the two types of SCPs involved in neurite outgrowth need to be in balance to produce a steady velocity of neurite outgrowth. We expanded previously published models of vesicle transport and microtubule growth, using experimental data from the literature to model in depth the various SCPs in each type and how they interacted. We developed analytical solutions that allowed us to calculate the relative relationships between different SCPs in a type that is needed to achieve overall balance between microtubule growth and membrane increase at the growth cone. Our models show that multiple loci within each type of SCPs are involved in obtaining balance between the two types for a specified velocity of neurite outgrowth. Parameter variation exercises allowed us to define the limits of variation within lower SCPs within a type that can be tolerated to maintain growth velocities. We conclude that as multiple SCPs come together to produce a dynamic whole cell response there is an identifiable hierarchy wherein there are redundancies at lower level SCPs, but critical quantitative interdependencies at the higher levels. peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/153569 doi: bioRxiv preprint first posted online Jun. 21, 2017;