Spatial and Temporal Sensing Limits of Microtubule Polarization in Neuronal Growth Cones by Intracellular Gradients and Forces

TL;DR

This study presents a computational model to understand how microtubules polarize in neuronal growth cones in response to chemical cues, revealing physical and biochemical limits of this process.

Contribution

It introduces a novel computational framework analyzing microtubule polarization limits and predicts minimal signal spread and polarization times in neuronal growth cones.

Findings

Minimal angular spread of chemical signals necessary for polarization

Maximum polarization driven by receptor signal magnitude

Physical and biochemical limits of microtubule polarization in growth cones

Abstract

Neuronal growth cones are the most sensitive amongst eukaryotic cells in responding to directional chemical cues. Although a dynamic microtubule cytoskeleton has been shown to be essential for growth cone turning, the precise nature of coupling of the spatial cue with microtubule polarization is less understood. Here we present a computational model of microtubule polarization in a turning neuronal growth cone (GC). We explore the limits of directional cues in modifying the spatial polarization of microtubules by testing the role of microtubule dynamics, gradients of regulators and retrograde forces along filopodia. We analyze the steady state and transition behavior of microtubules on being presented with a directional stimulus. The model makes novel predictions about the minimal angular spread of the chemical signal at the growth cone and the fastest polarization times. A regulatory reaction-diffusion network based on the cyclic phosphorylation-dephosphorylation of a regulator predicts that the receptor signal magnitude can generate the maximal polarization of microtubules and not feedback loops or amplifications in the network. Using both the phenomenological and network models we have demonstrated some of the physical limits within which the MT polarization system works in turning neuron.