A Molecular Model for Axon Guidance Based on Crosstalk between Rho GTPases

¹ Nara Institute of Science and Technology
² Osaka University

^* To whom correspondence should be addressed. E-mail: ishii{at}is.naist.jp.

Submitted on November 3, 2004
Revised on December 20, 2004
Accepted on 2 May 2005

	Abstract

To systematically understand the molecular events that underlie biological phenomena, we must develop methods to integrate enormous amount of genomic and proteomic data. The integration of molecular data should go beyond the construction of biochemical cascades among molecules to include tying the biochemical phenomena to physical events. For the behavior and guidance of growth cones, it remains largely unclear how biochemical events in the cytoplasm are linked to the morphological changes of the growth cone. We take a computational approach to simulate the biochemical signaling cascade involving members of the Rho family of GTPases and examine their potential roles in growth-cone motility and axon guidance. Based on the interactions between Cdc42, Rac, and RhoA, we show that the activation of a Cdc42-specific GEF resulted in switching responses between oscillatory and convergent activities for all three GTPases. We propose that the switching responses of these GTPases are the molecular basis for the decision mechanism that determines the direction of the growth cone expansion, providing a spatiotemporal integration mechanism that allows the growth cone to detect small gradients of external guidance cues. These results suggest a potential role for the crosstalk between Rho GTPases in governing growth-cone movement and axon guidance and underscore the link between chemodynamic reactions and cellular behaviors.

Key Words: Crosstalk, GTPase, axon guidance, gradient detection, simulation, ultrasensitivity

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