DEVELOPMENTAL NEUROSCIENCE Dissecting Growth Cone Guidance

The growth cones of developing neurons take s and turns that allow them to reach the appropriate target. Their path is guided by responses to attractive and repulsive cues from chemotropic ligands that they encounter along the way. These ligands activate receptors on the surface of the growth cone. Campbell and Holt describe new insights into the signaling pathways that are integrated to process such guidance cues. They report that in cultured Xenopus retinal growth cones, three different chemotropic ligands, netrin-1, semaphorin3A (Sema3A), and lysophosphatidic acid (LPA) stimulate distinct, but overlapping, signaling pathways. Netrin-1 and Sema3A activated the p42 and p44 mitogen-activated protein kinases (MAPKs). The p38 MAPK, normally associated with stress responses, was activated in cells treated with netrin-1 or LPA. Experiments with pharmacological inhibitors of the kinases indicated that the MAPK responses were necessary for axon guidance. Studies with antibodies to the active, cleaved form of caspase-3 revealed that caspase-3 was activated in response to LPA or netrin-1, and again, inhibitors were used to show that caspase activity was required for chemotropic responses in vitro. The authors discuss the potential role of caspase-3--better known as a component of pathways leading to apoptosis or cell death--in axon guidance. The authors further note similarities between the chemotropic pathways implicated in the present work with those thought to regulate synaptic plasticity.

C. S. Campbell, C. E. Holt, Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37, 939-952 (2003). [Online Journal]