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A Molecular Model for Axon Guidance Based on Cross Talk between Rho GTPases

Yuichi Sakumura ^*, Yuki Tsukada ^*, Nobuhiko Yamamoto  and Shin Ishii ^*

^* Graduate School of Information Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; and Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan

Correspondence: Address reprint requests to Shin Ishii, E-mail: ishii{at}is.naist.jp.

To systematically understand the molecular events that underlie biological phenomena, we must develop methods to integrate an 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 cross talk between Rho GTPases in governing growth-cone movement and axon guidance and underscore the link between chemodynamic reactions and cellular behaviors.

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