Feedback Mechanism for Microtubule Length Regulation by Stathmin Gradients

TL;DR

This paper presents a theoretical model of microtubule length regulation involving Rac1 and stathmin, revealing mechanisms for spatial gradient formation, bimodal length distributions, and bistability in MT dynamics.

Contribution

It introduces a novel model linking Rac1 and stathmin to microtubule regulation, highlighting mechanisms for spatial gradient formation and bistability in cell edge dynamics.

Findings

Bimodal microtubule length distributions near cell edges.

Bistability in microtubule length regulation with tubulin sequestering.

No bistability observed with catastrophe promoting stathmin.

Abstract

We formulate and analyze a theoretical model for the regulation of microtubule (MT) polymerization dynamics by the signaling proteins Rac1 and stathmin. In cells, the MT growth rate is inhibited by cytosolic stathmin, which, in turn, is inactivated by Rac1. Growing MTs activate Rac1 at the cell edge, which closes a positive feedback loop. We investigate both tubulin sequestering and catastrophe promotion as mechanisms for MT growth inhibition by stathmin. For a homogeneous stathmin concentration in the absence of Rac1, we find a switch-like regulation of the MT mean length by stathmin. For constitutively active Rac1 at the cell edge, stathmin is deactivated locally, which establishes a spatial gradient of active stathmin. In this gradient, we find a stationary bimodal MT length distributions for both mechanisms of MT growth inhibition by stathmin. One subpopulation of the bimodal length distribution can be identified with fast growing and long pioneering MTs in the region near the cell edge, which have been observed experimentally. The feedback loop is closed through Rac1 activation by MTs. For tubulin sequestering by stathmin, this establishes a bistable switch with two stable states: one stable state corresponds to upregulated MT mean length and bimodal MT length distributions, i.e., pioneering MTs; the other stable state corresponds to an interrupted feedback with short MTs. Stochastic effects as well as external perturbations can trigger switching events. For catastrophe promoting stathmin we do not find bistability.