How do Rho family GTPases direct axon growth and guidance? A proposal relating signaling pathways to growth cone mechanics

For a neuron to play its assigned role in a neural circuit, it has to extend elaborate projections, dendrites and axons, to make precise connections with specific target cells. The past decade has seen the identification of a vast diversity of molecules that assist in the guidance of axons toward their intended targets: guidance cues, growth cone receptors, signaling proteins (Tessier-Lavigne and Goodman, 1996; Song and Poo, 2001). But just how do all of these proteins work together to cause the axon to grow, stop, or turn in a specific direction? In this review, we examine this process from several different perspectives-cytoskeletal dynamics; biochemistry of intracellular signaling proteins; molecular analysis of axon guidance receptors-to try to collapse some of the apparent complexity of axon guidance into a more coherent picture. In particular, we will see how relatively simple and consistent manipulations of the kinetic constants of Rho family GTPases could account for many aspects of the cycle of actin dynamics that underlies axon growth and guidance. This review will intentionally be highly selective in its treatment of this subject in order to synthesize a simplified view that may be of value in directing further thinking and experiments.