Axon guidance: A compelling case for repelling growth cones

The guidance of axons to their targets represents a key stage in the assembly of the nervous system, linking the early inductive interactions that establish neuronal identity to the later steps of synapse formation. Neurons are required to extend axons through a variety of cellular environments, and the task of perceiving, integrating, and responding to the myriad signals present in the immediate vicinity of the axon falls to the growth cone, a sensory and motor apparatus located at the distal tip of the developing axon. Attempts to unravel the mechanisms of axonal guidance have centered on four main issues: the cellular strategies used to influence the rate of extension and the orientation of growth cones; the nature of molecules in the local environment of the axon that control growth cone behavior; the identity of receptors on the surface of growth cones that respond to these guidance cues; and the intracellular machinery that integrates multiple extracellular signals to produce the coordinated and directed response of growth cone navigation. The first wave of information on the cellular and molecular mechanisms of growth cone navigation emphasized positive influences on growth cone behavior through the identification of cell, axon, and substrate adhesion molecules that enhance the rate of axon extension and of chemoattractants that entice growth cones to distant targets. It took longer to appreciate that growth cone navigation also depends on negative influences, despite several early cellular assays that showed that contact with a variety of cell types inhibits growth cone motility (Walter et al., 1990; Goodman and Shatz, 1993; Schwab et al., 1993; Keynes and Cook, 1995). The first indications of the nature of proteins that cause growth cone inhibition have emerged over the past 2 years, and several papers in the current issues of Cell and Neuron now advance significantly the case that the guidance of axons, in both vertebrates and invertebrates, is dependent on proteins that inhibit or repel growth cones. These papers focus on two families of proteins, the semaphorinslcollapsins and the netrins. Intriguingly, the netrins have previously been implicated in the attraction of axons, suggesting that distinctions in the nature of guidance cues reside more in the response properties of growth cones than in the identity of environmental signals. Cellular Origins of Growth Cone inhibition In the 198Os, assays of growth cone behavior and axon navigation in vitro began to suggest the existence of signals that guide axons by repelling growth cones (Kapfhammer and Raper, 1987; Walter et al., 1987; Schwab et al., 1993; Keynes and Cooke, 1995). Of critical importance for the identification of relevant molecules was the develMinireview