Introduction-1890 to the present: beginning the third century of the growth cone

Almost 10 years ago, we co-edited with Stan Kater a monograph (“The Nerve Growth Cone,” Raven Press, 1991) that brought together a number of then cuttingedge contributions on this fascinating structure. This monograph resulted from a meeting in honor of the 100th anniversary of Santiago Ramon y Cajal’s initial publication on the growth cone. In the decade since that meeting, new information has accreted rapidly, particularly in the identification of many new molecular components of the sensory-motor functions of the growth cone, whose remarkable dynamic properties have come into sharper focus thanks to superb new techniques for imaging and analysis. As we begin a new decade, century and millenium, it seemed to use timely to review research on the nerve growth cone and look ahead to what remains to be discovered about a structure of such central important to neural development and regeneration. Cajal’s 1890 published drawings and verbal descriptions of growth cones that he observed in fixed preparations of embryonic chick spinal cord are truly remarkable. The combination of his virtuoso use of the Golgi method with his keen observation and inspired insight led Cajal to predict accurately the exploratory behaviors of living growth cones from the still images. Furthermore, he proposed that growth cones guide elongating axons by “sniffing out” targets and “climbing” along pathways to proper synaptic sites. His predictions of growth cone behavior were affirmed 20 years later by Ross Harrison, the first to report observing living growth cones in explants of amphibian spinal cords. In the early 1930s, Carl Spiedel was the first to study growth cones in vivo, in the transparent tails of developing amphibian embryos immobilized on a microscope stage. These early studies of the growth cone already revealed the extraordinary motility of filopodial and lamellipodial protrusions, constantly active as growing axons advance, retreat or split into multiple branches, each led by its own growth cone. These dynamic protrusions appeared to behave like probing antennae, continually exploring their local environments for cues to follow to the axons’ predetermined targets. Roger Sperry’s studies of the accuracy of neural development and regeneration lead him to propose that regularly ordered synaptic connections arose from the matching of chemical labels between incoming axonal growth cones and target neurons. This hypothesis played a major role in inspiring further investigations to elucidate the molecules on axons, growth cones, and target cells that comprise the labels and signposts that lead growth cones to their proper destinations. As cell biological discovery accelerated from the 1950s on, it was recognized that the behaviors of growth cones, like those of motile cells, were based on the dynamic properties of actin filaments and microtubules. These cytoplasmic polymers undergo continual reorganization to change cell shapes and generate mechanical forces that move cells, cellular extensions, and intracellular contents. It also became clear that the movements of growth cones, like those of motile connective tissue cells and leukocytes, were regulated by contacts with other cells and surfaces and by gradients of diffusible molecules. Beginning in the 1970s, biochemical characterizations of molecules that promote neuronal adhesion and genetic studies of invertebrates to identify genes that code for proteins that regulate neuronal growth have converged to generate a rich catalogue of molecules that control growth cone navigation. This endeavor was facilitated by the realization that many of