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Multiple roles of eph receptors and ephrins in neural development

Nature Reviews Neuroscience volume 2, pages 155–164 (2001)Cite this article

Key Points

  • The control of cell movement is essential for forming and stabilizing the spatial organization of tissues and cell types during development. Eph receptor tyrosine kinases (RTKs) and their ephrin ligands have emerged as important regulators of cell movements in many tissues and at multiple stages of patterning.

  • Eph receptors are transmembrane RTKs that are activated by clustering that occurs on binding to membrane-bound ephrin ligands. In vertebrates, there are 14 Eph receptor and 8 ephrin family members, and the ephrins fall into two structural classes, ephrin-A and ephrin-B, on the basis of their means of anchorage to the plasma membrane. With a few exceptions, ephrin-As bind to the EphA class of receptors, and ephrin-Bs bind to the EphB class.

  • The ephrins also transduce signals on binding to an Eph receptor, such that each component can act both as 'receptor' and 'ligand' in cell-contact-dependent signalling. Eph receptors and ephrins are expressed in complex patterns throughout vertebrate development. Complementary expression of interacting Eph receptors and ephrins can lead to bidirectional activation at the interface, whereas overlaps in expression lead to persistent activation within the expression domain.

  • One important role of reciprocal expression of Eph receptors and ephrin-B proteins is in unidirectional or bidirectional repulsion at boundaries, preventing cells or axons from entering inappropriate territory. In the nervous system, this mechanism is involved in stabilizing the organization of hindbrain segments, and in the guidance of migrating neural crest cells and neuronal growth cones.

  • A related role is in the establishment of topographic maps of neuronal projections, including the anteroposterior axis of the retinotectal map. This involves graded expression of EphA receptors in retinal neurons, which underlies a graded sensitivity of their growth cones to a gradient of ephrin-mediated repulsion in the tectum/superior colliculus. There is evidence that the degree of repulsion acts to differentially bias retinal axons in a competition for space in the tectum.

  • Several components downstream of Eph receptor activation are implicated in pathways that control the local depolymerization of the actin cytoskeleton that underlies repulsion. Eph receptors can also downregulate the function of integrins involved in cell attachment to extracellular matrix, whereas in other contexts they can upregulate integrin-mediated adhesion. Furthermore, ephrin-A activation upregulates integrin function. An important question is: what mechanisms underlie a repulsion versus adhesion response to Eph receptor activation?

  • Evidence is emerging for roles of Eph receptors and ephrins in regulating other cellular responses, such as communication through gap junctions, cell proliferation and cell death. Eph receptors and ephrins might thus couple the regulation of repulsion and adhesion to other cellular responses involved in patterning. In addition, Eph receptors and ephrins localized at synapses might be involved in regulation of synaptic properties, such as plasticity.

Abstract

The control of cell movement during development is essential for forming and stabilizing the spatial organization of tissues and cell types. During initial steps of tissue patterning, distinct regional domains or cell types arise at appropriate locations, and the movement of cells is constrained in order to maintain spatial relationships during growth. In other situations, the guidance of migrating cells or neuronal growth cones to specific destinations underlies the establishment or remodelling of a pattern. Eph receptor tyrosine kinases and their ephrin ligands are key players in controlling these cell movements in many tissues and at multiple stages of patterning.

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Figure 1: Eph receptors and ephrins.
Figure 2: Repulsion at boundaries.
Figure 3: Gradients and mapping.
Figure 4: Biochemical effectors of repulsion and adhesion.

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Acknowledgements

I am grateful to Qiling Zu for comments on this review.

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Authors and Affiliations

  1. Division of Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill , NW7 1AA, London, UK

    David G. Wilkinson

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  1. David G. Wilkinson
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DATABASE LINKS

Eph RTK family

ephrin

Nck

RasGAP

Src

WASP

SHEP1

R-Ras

Raf1

SHP2

NIK

Kuzbanian

LMW-PTP

PDGF

FGF

FGFR

ENCYCLOPEDIA OF LIFE SCIENCES

Ephrins

Vertebrate central nervous system: pattern formation

Axon guidance

Glossary

GLYCOSYLPHOSPHATIDLYLINOSITOL LINKAGE

A molecular mechanism for attaching a cell membrane protein to the lipid bilayer. It consists of a glycerophospholipid molecule, which is attached to the protein through a carbohydrate chain.

HOMOPHILIC CELL–CELL ADHESION

Adhesion that is mediated through attraction between identical molecules displayed by different cells.

SOMITES

Paired blocks of mesoderm along the vertebrate body axis that differentiate into dermis, bone and muscle.

DORSAL ROOT GANGLIA

The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. These cell bodies are surrounded by satellite glial cells, which share much in common with the Schwann cells that ensheath peripheral axons. Very few synapses have been observed in these ganglia.

SYMPATHETIC GANGLIA

Clusters that contain the neurons of the sympathetic nervous system, which is responsible for such physiological effects as reduction of digestive secretions, vasoconstriction and an increased heart rate, thereby opposing the effects of the parasympathetic nervous system.

BRANCHIAL ARCH

In the higher vertebrate embryo, one of a series of arches, populated by neural crest cells, that develop into structures of the ear, neck and face. The corresponding structures in fish and amphibians, sometimes referred to as gill arches, are made of bone or cartilage and are located on either side of the pharynx.

ANTERIOR COMMISSURE

A tract of nerve fibres connecting the two cerebral hemispheres.

INTEGRINS

A large family of heterodimeric transmembrane proteins that act as receptors for cell adhesion molecules.

ANGIOGENESIS

The formation of blood vessels, such as occurs during embryogenesis, tissue repair or tumorigenesis.

VOMERONASAL AXONS

Axons that project from the vomeronasal organ to the accessory olfactory bulb, forming part of the relay pathway for pheromone detection.

SH2 DOMAIN

A ∼100-amino-acid domain that binds to phosphotyrosine-containing motifs and is found in many proteins involved in signal transduction.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. They can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains.

MEMBRANE RAFT MICRODOMAINS

Domains of the plasma membrane enriched in sphingolipids and cholesterol. They incorporate lipid-conjugated proteins and thus serve to assemble proteins involved in signal transduction.

WISKOTT–ALDRICH SYNDROME PROTEIN

A protein that is thought to provide a link between signalling pathways and the actin cytoskeleton. Mutations in the human WASP gene cause Wiskott–Aldrich syndrome, a disorder characterized by immunodeficiency and defects in haematopoiesis.

DOMINANT-NEGATIVE

A mutant protein that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

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Wilkinson, D. Multiple roles of eph receptors and ephrins in neural development. Nat Rev Neurosci 2, 155–164 (2001). https://doi.org/10.1038/35058515

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