Among the many extraordinary features of nervous system development, one of the most fascinating is the ability of growing axons to navigate through a complex cellular embryonic terrain to find appropriate synaptic partners that may be millimeters or even centimeters away. In 1910, Ross G. Harrison, who first observed axons extending in a living tadpole in vitro, noted:

Harrison's observations indicate the central features of axonal growth. First, the energy and power of growing axons reflect the cellular properties of the growth cone, a specialized structure at the tip of the extending axon. Growth cones are highly motile structures that explore the extracellular environment, determine the direction of growth, and then guide the extension of the axon in that direction. The primary morphological characteristic of a growth cone is a sheetlike expansion of the growing axon at its tip called a lamellapodium. When examined in vitro, numerous fine processes called filopodia rapidly form and disappear from the terminal expansion, like fingers reaching out to touch or sense the environment (Figure 23.1). The cellular mechanisms that underlie these complex searching movements have become a focus of cell biological studies of axon growth and guidance. Such movements are thought to reflect rapid, controlled rearrangement of cytoskeletal elements—particularly molecules related to the actin cytoskeleton—which modulate the changes in growth cone shape and ultimately its course through the developing tissues.

Santiago Ramón y Cajal, Harrison's contemporary, noted that when growth cones move along an established pathway pioneered by other axons, they tend to be simple in shape. In contrast, when a growing axon first extends in a new direction or reaches a region where a choice must be made about the direction to take, the structure (and presumably motility) of its growth cone undergoes dramatic changes. The growth cone flattens and extends numerous filopodia, much as it does in a culture dish, suggesting an active search for appropriate cues to direct subsequent growth. These changes of growth cone shape at “decision points” have been observed in both the peripheral and central nervous system. In the periphery, growth cones of motor neurons undergo shape changes as they enter the primordia of muscles in immature limbs, presumably seeking appropriate targets in the developing musculature. In the central nervous system, growth cones in developing olfactory and optic nerves also change shape when they reach critical points in their trajectories. Of particular functional significance is the decision made by subsets of retinal axons at the optic chiasm. The growth cones of retinal axons slow down and acquire a complex shape as they “choose” whether or not to cross the midline (Figure 23.2).