Review
Axon guidance: receptor complexes and signaling mechanisms

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Abstract

The generation of a functional neuronal network requires that axons navigate precisely to their appropriate targets. Molecules that specify guidance decisions have been identified, and the signaling events that occur downstream of guidance receptors are beginning to be understood. New research shows that guidance receptor signaling can be hierarchical — one receptor silencing the other — thereby allowing navigating growth cones to interpret opposing guidance cues. Among the known intracellular signaling molecules shared by all guidance receptor families, Rho GTPases appear to be primary regulators of actin dynamics and growth cone guidance. Novel effector molecules complete the picture and suggest additional signaling mechanisms.

Introduction

Navigating axons express receptors for guidance molecules presented by neighboring cells. Activation of and subsequent signaling by these receptors determines whether or not the axon grows towards a target (attraction) or away from it (repulsion) [1]. Basic guidance principles are conserved throughout evolution, so that different approaches — genetic, cell and molecular biological, and biochemical — in different organisms — from nematodes to mammals — have synergized to push our understanding of axonal guidance forward at amazing speed. At least four conserved families of guidance molecules with important developmental functions have been identified: semaphorins, Slits, and netrins, which are all secreted molecules (except for some semaphorins), and ephrins, which are tethered to the plasma membrane (reviewed in 2., 3., 4., 5., 6., 7., 8., 9., 10., 11.). The functions of these axon guidance molecules are not limited to axon guidance, as Slit plays important roles in mesodermal cell migration 12., 13., ephrins are important in somitogenesis, vasculogenesis (reviewed in [9]), and synaptic plasticity 14., 15., 16., and semaphorins are crucial for heart and bone development [17]. Ligand activities are transduced by receptors and their signaling effectors. This review focuses on recent advances made in our understanding of receptor crosstalk and signaling mechanisms.

Section snippets

Semaphorins

Semaphorins comprise a large, 20 member family of soluble and membrane-tethered molecules that are critically involved in axon guidance both in invertebrates and in vertebrates. They share a conserved, 500 amino acid long region: the ‘Sema’ domain. Many neuronal cells respond to semaphorins including sympathetic, motor, cerebellar, hippocampal, olfactory, corticospinal and dorsal root ganglion (DRG) neurons (reviewed in [18]).

Repulsive signals elicited by semaphorins are exerted by two receptor

Rho GTPases downstream of plexins

Rho GTPases provide another mode of signaling particularly appreciated in axon guidance. Several laboratories have provided biochemical and genetic evidence that Rho and its family members Rac1 and Cdc42 play distinct roles in semaphorin receptor signaling. Rho GTPases function as molecular switches, cycling between an active GTP-bound and an inactive GDP-bound form. Early work gave the first indication that Rac1 may directly mediate F-actin reorganization downstream of Sema3A/PlexA1 [22]. In

Slit/Robo system

Neuropilin receptors are expressed by commissural neurons and are required to navigate commissural axons across the midline of the CNS to their rostral targets after midline crossing [32]. In this system, class 3 semaphorins act in concert with another class of repellent proteins, the Slits, to prevent commissural axons from recrossing or lingering at the midline. Drosophila Slit is a large extracellular matrix protein expressed by midline glia cells and acts as a long-range chemorepellent for

Netrins

The CNS midline not only expresses repulsive factors, such as Slits and semaphorins, but also a small family of secreted proteins, termed netrins, which attract commissural axons before midline crossing. Netrin-induced attraction is mediated by the DCC (deleted in colorectal cancer) family of receptors that include Frazzled in Drosophila, UNC40 in C. elegans, and DCC and neogenin in vertebrates [11]. Their cytoplasmic domains contain three regions of high sequence homology across species, named

Ephrins

Ephrin ligands are tethered to the plasma membrane either by a glycosylphosphatidylinositol (GPI) anchor (all invertebrate ephrins, vertebrate ephrinA1–A5) or by a transmembrane segment (vertebrate ephrinB1–B3). Whereas invertebrates have only one receptor for ephrins, vertebrate ephrin receptors fall into two subclasses: EphA receptors (EphA1–A8) and EphB receptors (EphB1–B4), depending on whether they interact with A-type or B-type ephrins (reviewed in [9]). EphrinB ligands and EphB receptors

Eph effectors

Previous work, mainly using overexpression systems, identified a wide array of potential downstream targets of Eph receptors, including Src family kinases, RasGAP, phospholipase Cγ and others (reviewed in [49]). A unique feature of Eph among the family of receptor tyrosine kinases is their inability to stimulate cellular growth and proliferation. A potential molecular basis of this phenomenon has recently been identified [57]. Using different cell lines and primary cells, Miao et al. [57]

Conclusions and future directions

A variety of receptors and their respective ligands act in concert or against each other to achieve finely tuned axon guidance. Among the signals downstream of these receptors, Rho GTPases seem to have a crucial role in the regulation of actin dynamics. Several new molecules have been identified and add extra layers of intricacy to axon guidance mechanisms. However, at the same time, these new molecules hint to novel mechanisms for fast, local, and very precise responses of growth cones in

Update

As described in more detail above, the binding of activated RacGTP to PlexB1 sequesters Rac and inhibits its binding to and subsequent activation of PAK 24., 26••.. A more recent report by Vikis et al. [63] confirms these observations for the mammalian system downstream of Sema4D-activated PlexB1. Using overexpression experiments in COS and HEK293 cells, these authors demonstrate that the binding of activated RacGTP to PlexB1 additionally increases the cell surface expression of PlexB1 and

Acknowledgements

We thank BJ Dickson, F Helmbacher and GA Wilkinson for critically reading the manuscript and for helpful discussions. Work in the lab was supported by grants from the Human Frontiers Science Programme Organization, the Deutsche Forschungsgemeinschaft and the Max-Planck Society.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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