A molecular model for axon guidance based on cross talk between rho GTPases.
A molecular model for axon guidance based on cross talk between rho GTPases.
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DOI：
10.1529/biophysj.104.055624
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发表时间：
2005-08
影响因子：
3.4
通讯作者：
Y. Sakumura;Yuki Tsukada;N. Yamamoto;Shin Ishii
中科院分区：
文献类型：
--
作者：
Y. Sakumura;Yuki Tsukada;N. Yamamoto;Shin Ishii
为了系统地理解生物现象背后的分子事件，我们必须开发整合大量基因组和蛋白质组数据的方法。分子数据的整合应该超越分子间生化级联的构建，包括将生化现象与物理事件联系起来。对于生长锥的行为和指导，在很大程度上仍然不清楚细胞质中的生化事件如何与生长锥的形态变化相关联。我们采用计算方法来模拟涉及Rho家族的GTP酶成员的生化信号级联反应，并研究它们在生长锥运动和轴突指导中的潜在作用。基于Cdc42，Rac和RhoA之间的相互作用，我们发现，Cdc42特异性GEF的激活导致所有三种GTP酶的振荡和收敛活动之间的切换响应。我们建议，这些GTP酶的开关响应的决定机制，决定生长锥扩张的方向的分子基础，提供时空整合机制，使生长锥检测小梯度的外部指导线索。这些结果表明Rho GTPases之间的串扰在控制生长锥运动和轴突引导中的潜在作用，并强调了化学动力学反应和细胞行为之间的联系。
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.