The molecular biology of axon guidance

Neuron, 1996

Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.

Cell, 1995

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.

F1000 biology reports, 2009

One of the challenges to understanding nervous system development is to establish how a fairly limited number of axon guidance cues can set up the patterning of very complex nervous systems. Most of the recent insights relevant to guidance mechanisms have come from cell biologists focusing on processes and molecular machinery controlling the guidance responses in the growth cone.

Advances in Experimental Medicine and Biology, 2007

Current Opinion in Neurobiology, 2002

Current Opinion in Neurobiology, 2006

The intricate connections of the nervous system are established, in part, by elongating axonal fibers that are directed by complex guidance systems to home in on their specific targets. The growth cone, the major motile apparatus at the tip of axons, explores its surroundings and steers the axon along a defined path to its appropriate target. Significant progress has been made in identifying the guidance molecules and receptors that regulate growth cone pathfinding, the signaling cascades underlying distinct growth cone behaviors, and the cytoskeletal components that give rise to the directional motility of the growth cone. Recent studies have also shed light on the sophisticated mechanisms and new players utilized by the growth cone during pathfinding. It is clear that axon pathfinding requires a growth cone to sample and integrate various signals both in space and in time, and subsequently to coordinate the dynamics of its membrane, cytoskeleton and adhesion to generate specific responses.

Development, 2006

The normal function of the nervous system requires that the constituent neurons are precisely `wired together'. During embryogenesis, each neuron extends an axonal process, which can navigate a considerable distance to its target. Although a number of the receptors and guidance signals that direct axonal growth have been identified, less is known about the transcription factors that regulate the expression of these molecules within the neuron and its environment. This review examines recent studies in vertebrates and Drosophila that address the identity of the transcription factors that either control the repertoire of guidance receptors and signals that permits an axon to take a particular trajectory or act themselves as novel extracellular guidance factors.

Cold Spring Harbor perspectives in biology, 2010

Axons follow highly stereotyped and reproducible trajectories to their targets. In this review we address the properties of the first pioneer neurons to grow in the developing nervous system and what has been learned over the past several decades about the extracellular and cell surface substrata on which axons grow. We then discuss the types of guidance cues and their receptors that influence axon extension, what determines where cues are expressed, and how axons respond to the cues they encounter in their environment.

Current Biology, 1999

Axon guidance depends on the transduction of extracellular guidance cues into motile responses by the axonal growth cone. Recent studies in vivo have elucidated mechanisms required for this process that involve kinases and phosphatases, calcium dynamics and remodeling of the actin cytoskeleton.

Seminars in Neuroscience, 1991

The potential importance of contact inhibition for neural development and regeneration has only recently been recognised. Growth cones have been shown to undergo abrupt collapse following contact with various cell types in vitro, including other neurons, and the collapse phenomenon is now being exploited to isolate and characterise the relevant molecules. Identifying the underlying mechanisms, which may involve ligand-receptor interactions, will be necessary for a full understanding of both axon guidance and the failure of axons to regenerate in the CNS of higher vertebrates. Key words : contact inhibition / glycoconjugates / growth cone / nerve regeneration / neural development CONTACT inhibition of cell movement has been a familiar phenomenon since its original description in fibroblast cultures by Abercrombie and Heaysman in 1954. 1 Only more recently, however, have neurobiologists begun seriously to consider the possibility that contact inhibition at nerve endings may play an important role in shaping the developing and mature nervous system. 2 It is easy to suggest (as we do below) that developmental processes such as axon guidance, synapse formation and synapse elimination may involve inhibitory as well as adhesive interactions. It is also possible that the failure of regeneration in the mature CNS of higher vertebrates results, at least in part, from inhibitory interactions between axons and their immediate environment. Our purpose here is to show that there is now strong evidence that inhibitory or repulsive interactions are implicated in neural development and regeneration, that this is apparent in several different experimental systems, and that the way is now open for a detailed understanding of the molecular mechanisms involved .