The formidable task of accurately establishing the connections of the central nervous system (CNS) is shared by both vertebrates and invertebrates and appears to be conserved throughout phylogeny. For example, in adult humans, the nervous system consists of more than a billion neurons, each connecting to over 1000 target cells in intricate circuits (see The Development and Evolutionary Expansion of the Cerebral Cortex in Primates, Primate Brain Evolution in Phylogenetic Context, The Evolution of Parallel Visual Pathways in the Brains of Primates, Brain Size in Primates as a Function of Behavioral Innovation, Constraints on Brain Size: The Radiator Hypothesis). The very simple nervous system of the nematode Caenorhabditis elegans contains only 302 neurons, yet faces similar challenges with respect to forming appropriate neuronal connections. Indeed, despite millions of years of evolutionary separation, most of the key molecules that mediate the formation of the nervous system in organisms as different as humans and C. elegans are highly conserved. These neuronal connections are generated during embryogenesis in a highly specific and precise manner, which is fundamental for the proper functioning of the adult nervous system.

As development progresses, neurons connect to each other in their local environment with dendrites and to distant targets through the extension of an axon. The process of dendritogenesis is a very complex field (reviewed in Sanes et al., 200( ) and, in this article, we will focus solely on axon development. Observations of developing axonal projections in vivo have revealed that axons extend toward their targets in a highly stereotyped and direct manner (reviewed in Sanes et al., 2000). Axon pathfinding is controlled by proteins present in the environment explored by each growing axon, which is tipped at its leading edge by a specialized structure called the growth cone (Ramon y Cajal, 1890). The growth cone receives and integrates local attractive and repulsive signals presented by cells in the environment, resulting in directed guidance toward its appropriate target.

How does the growth cone accomplish this? Understanding the molecular interactions between a growth cone and the environment presents a great challenge for neurobiologists. Our current knowledge comes from studies of both vertebrates and invertebrates, with each group of organisms offering specific advantages toward the elucidation of this process. For example, invertebrates are commonly used for genetic mutation screens to identify genes of interest in axon pathfinding, whereas vertebrate models have provided useful systems in unraveling the functional mechanisms of these genes.

In this article we will describe the general aspects of axon pathfinding. We will first discuss the molecular characteristics of the growth cone and some general concepts of axon guidance; second, we will describe the main families of guidance cues; third, we will focus on two model systems commonly used to study axon pathfinding, the vertebrate visual system and the CNS midline choice point; and finally, we will discuss some mechanisms known to modulate axon pathfinding.

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