Axon guidance mechanisms and molecules: lessons from invertebrates

Key Points

• During embryonic development, axons travel considerable distances to reach their final targets in a stereotyped manner. The rapid advances in our understanding of this process have been aided by the use of invertebrate systems. Organisms such as Drosophila and C. elegans have been particularly useful owing to their relatively simple nervous systems and their susceptibility to rigorous genetic analysis.

• A key strategy during axonal pathfinding is to break the distance to the target into a series of smaller trajectories between guidepost cells, the existence of which was discovered in the grasshopper limb bud. Netrin and its receptors are important mediators of the interaction between guidepost cells and axons, and genetic studies have aided in outlining the signalling cascade that mediates the action of netrin.

• Roundabout (Robo) and Slit form part of a related signalling system that is crucial for axonal pathfinding. Their main role is to regulate the midline crossing of axons in the Drosophila nervous system, and a series of genetic studies have led to the definition of the intracellular cascade that might mediate their effect.

• Pre-existing axons are important in guiding subsequent axon outgrowth, as follower axons often fasciculate with pioneers to reach their target area. It has been proposed that tracts have different molecular labels that subsequent axons can recognize. Various molecules, including neuroglian, N-cadherin and the fasciclins, have been identified that fulfil this labelling role.

• Defasciculation is as important as fasciculation for pathfinding, and several additional molecules have been identified as being involved in this process. They include the semaphorins, Beaten path, Off-track and others. The intracellular routes whereby these molecules mediate defasciculation have begun to be charted.

• Analysis of the Drosophila eye has led to the identification of additional guidance molecules that might not have been identified by the use of conventional phenotypic screens. Specifically, it has been useful for the identification of intracellular signalling elements that contribute to axon guidance.

• Despite the identification of many molecules that underlie axon guidance, there might be others. For example, we know little about how axons integrate the simultaneous cues that they receive to generate a single response, and how they adapt their responses as they move along their pathway. Answers to these questions will require the combined use of the experimental advantages of both invertebrate and vertebrate systems.

Abstract

Vertebrates and invertebrates share the formidable task of accurately establishing the elaborate connections that make up their nervous systems. Researchers investigating this process have the challenge of identifying the molecules and mechanisms that underlie this process. Each group of organisms offers their own advantages for piecing together the conserved constituents. Broadly speaking, the invertebrates have allowed the discovery of relevant genes through classical genetic screens for mutations that affect the process of axon guidance, whereas vertebrates provide numerous systems for the elaboration of the functional mechanisms. Here, we focus on the role of invertebrates in characterizing the molecular mechanisms of axon guidance.