During development of the nervous system, neurons and growth cones migrate toward their targets by responding to environmental cues. Interactions between cell surface receptors and these extracellular signals elicit changes in the neuronal cytoskeleton that cause a growth cone to turn either away from a repellant or toward an attractant molecule. The Eph family of receptor tyrosine kinases and ephrins, their membrane-bound ligands, guide axons during formation of complex neuronal circuitry. These receptors alter the dynamics of the actin cytoskeleton by controlling the activity of the small GTP-binding proteins RhoA, Rac, and Cdc42.
Sahin et al. report that in the absence of ephrin stimulation, EphA4 is associated with ephexin1, a guanine nucleotide exchange factor (GEF) located in growth cones that activates RhoA, Rac1, and Cdc42 to promote axon outgrowth. Upon activation with ligand, EphA4 induced phosphorylation of ephexin1 by a Src family tyrosine kinase. The modification enhanced ephexin's exchange activity on RhoA, resulting in growth cone collapse and axon repulsion in cultured neurons. Neurons from transgenic mice lacking ephexin1 had shorter axons and did not exhibit the repulsive response to ephrin.
Cowan et al. also report that Vav2, another GEF located in growth cones that acts on RhoA, Rac, and Cdc42, is important for Eph-mediated axon guidance. Eph receptor-ephrin interaction mediates cell-cell contact. However, upon activation by ligand, activated Eph receptors are internalized in a Rac-dependent manner, disrupting cell-cell associations and promoting the repulsive response. Activated Eph receptors associated with Vav2. The exchange factor became phosphorylated on tyrosine, increasing its activity. This corresponded with endocytosis of Eph receptors. Vav-deficient neurons showed abnormal axon projections, and stimulation with ephrin molecules failed to induce endocytosis of Eph receptors or growth cone collapse.
The studies suggest that by engaging specific GEFs to coordinate different intracellular processes, Eph receptors can promote highly localized changes in growth cones to facilitate accurate axon pathfinding.
M. Sahin, P. L. Greer, M. Z. Lin, H. Poucher, J. Eberhart, S. Schmidt, T. M. Wright, S. M. Shamah, S. O'Connell, C. W. Cowan, L. Hu, J. L. Goldberg, A. Debant, G. Corfas, C. E. Krull, M. E. Greenberg, Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46, 191-204 (2005).[Online Journal]
C. W. Cowan, Y. R. Shao, M. Sahin, S. M. Shamah, M. Z. Lin, P. L. Greer, S. Gao, E. C. Griffith, J. S. Brugge, M. E. Greenberg, Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron 46, 205-217 (2005). [Online Journal]