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Mechanisms of ephrin–Eph signalling in development, physiology and disease

Key Points

  • Eph Tyr kinases and ephrins can simultaneously act as receptors and ligands, allowing unidirectional or bidirectional signalling, which in turn can lead to parallel and antiparallel signalling modes between two neighbouring cells (in trans configuration). Ephs and ephrins can also interact on the surface of the same cell (in cis), and this attenuates Eph signalling, possibly by inhibiting the formation of Eph clusters.

  • Eph-triggered cellular responses lead to cytoskeletal rearrangements, such as the collapse of the cytoskeleton, by controlling the balance between small GTPase activation and inactivation. Eph forward signalling often results in cell repulsion, whereas ephrin reverse signalling elicits either cell repulsion or adhesion.

  • The formation of topographic maps, in which the positions of projection neurons relative to one another are maintained in the relative positions of the innervated targets, is mediated by ephrin–Eph signalling.

  • Ephrin–Eph signalling regulates cell migration in neurons, allowing the cells to reach their final destination, guides axons along intermediate choice points to reach their final targets, and mediates synapse formation and plasticity.

  • In blood and lymphatic vasculature, ephrin–Eph signalling establishes borders between different compartments and helps the remodelling process by regulating the effects of vascular growth factors.

  • Ephrin–Eph signalling plays complex parts in several adult stem cell niches and can be both inhibitory and beneficial for central and peripheral nervous system regeneration, respectively.

  • Ephrin–Eph signalling also has complex roles in cancer by controlling tissue architecture and cellular motility. These proteins are therefore important targets in therapies against various human diseases.

Abstract

Eph receptor Tyr kinases and their membrane-tethered ligands, the ephrins, elicit short-distance cell–cell signalling and thus regulate many developmental processes at the interface between pattern formation and morphogenesis, including cell sorting and positioning, and the formation of segmented structures and ordered neural maps. Their roles extend into adulthood, when ephrin–Eph signalling regulates neuronal plasticity, homeostatic events and disease processes. Recently, new insights have been gained into the mechanisms of ephrin–Eph signalling in different cell types, and into the physiological importance of ephrin–Eph in different organs and in disease, raising questions for future research directions.

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Figure 1: Domain composition and signalling modes of Ephs and ephrins.
Figure 2: Intracellular signalling pathways of Ephs and ephrins.
Figure 3: Visual system development controlled by ephrin–Eph signalling.
Figure 4: Spinal motor neuron axon guidance in the limb controlled by multiple modes of ephrin–Eph signalling.
Figure 5: Blood vessel development and adult neurogenesis are regulated by ephrin–Eph signalling.
Figure 6: Maintenance of the intestinal stem cell niche and bone homeostasis are regulated by ephrin–Eph signalling.

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Acknowledgements

R.K. is supported by the Max Planck Society and by grants from the European Research Council (ERC) and the Deutsche Forschungsgemeinschaft (Munich Cluster for Systems Neurology, SyNergy). A.K. is supported by the Canadian Institutes of Health Research, National Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation, Brain Canada and the W. Garfield Weston Foundation. The authors thank Daniel Morales for critical comments on the manuscript.

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Glossary

Axon guidance

A process during which neurons extend axonal processes (see definition of neurons, below) that are directed towards their innervation targets such as other neurons or muscles.

Neurons

Specialized cells transmitting nerve impulses. Neurons comprise a cell body containing the nucleus; dendrites, which are short processes extending from the cell body that receive nerve impulses; and an axon, which is a long process that transmits nerve impulses to the neuron's postsynaptic target.

Axonal growth cones

Highly motile, fan-like structures at the tip of the extending axons. They often contain receptors for axon guidance cues, signalling from which re-organizes the underlying actin cytoskeleton, resulting in changes in the direction of axon extension.

Sterile-alpha motif

(SAM). A protein domain with a predicted helical structure that can induce protein–protein interactions.

Rho GTPases

Molecular switch proteins that belong to the Ras, Rho, Rab, Arf and Ran families, which are known for their control of actin polymer stability and for generally coupling cell membrane receptor function to cytoskeleton dynamics.

Synapse

A narrow contact point across which a neuron sends chemical and electrical signals to its postsynaptic target, frequently another neuron.

Neural tube closure

An early embryonic development event during which the ectodermal layer that contains the precursors of the nervous system forms an elongated trough, the walls of which eventually rise up and fuse at their dorsal edge, forming the neural tube.

Cajal–Retzius cells

Cells with complex morphologies in the most superficial layer of the cortex. They initially disperse from discrete developing brain regions in a dimension tangential to the surface of the cortex to produce an even-spaced tiling. They secrete Reelin, a large protein that is important for the radial migration of cortical neurons.

Cerebral cortex

The outer layer of the brain, which is more prominent in higher vertebrates and is composed of grey and white matter.

Cortical interneurons

Diverse set of GABAergic inhibitory neurons with relatively short axons that regulate the activity of excitatory pyramidal cells.

Growth cone turning

A response arising from the stabilization or collapse of the actin cytoskeleton in growth cones. Turning is induced by axonal guidance cues, which trigger attraction or repulsion of growth cones.

Thalamus

A structure located at the base of the brain, functioning as a relay station for sensory information on its way to the cerebral cortex.

Optic chiasm

A structure at the midline of the vertebrate nervous system, where nerves originating in both retinas converge and cross to innervate brain structures (mostly) on the side of the nervous system opposite to the eye.

Locomotor behaviour phenotypes

Behavioural phenotypes that are characterized by abnormal animal movement. Here, it mainly refers to phenotypes caused by defects in spinal cord neuronal circuits concerned with coordinated activation of muscles involved in locomotion.

Topographic maps

In reference to the distribution of parts or features on the surface of animals. Here, this term refers to the orderly distribution of nerves originating in sensory organs, such as the retina, where the relative position of nerves at the origin (retina) is maintained at their target (for example, the superior colliculus), thus providing the nervous system with an internal representation of the external world.

Projection neurons

Neurons, the axons of which extend a long distance within the nervous system relative to local interneurons that innervate nearby targets.

Motor neurons

Neurons, the synaptic targets of which lie outside the nervous system, including those that innervate muscles and ganglia of the autonomic nervous system.

Dendritic branching

Complex branches, similar to those of trees, that form when dendritic processes extend from the neuronal cell body.

Filopodia

Thin cytoplasmic extensions found at the forefront of migrating cells or growth cones.

Angiogenesis

A physiological process that generates new blood vessels from pre-existing ones. Sprouting is a form of angiogenesis in which the vessel-forming cells, the endothelial cells, proliferate into the surrounding tissue and form sprouts that eventually form loops to become a new vessel. Pruning describes the cropping and removal of existing vessels.

Lymphangiogenesis

A physiological process that generates new lymphatic vessels from pre-existing ones.

Frontonasal neural crest

Subpopulation of neural crest cells that gives rise to certain midfacial bones.

Neural crest

A multipotent migratory stem cell population in vertebrates that generates a diverse cell lineage, including peripheral neurons and glia, melanocytes, smooth muscle, craniofacial cartilage and bone.

Stem cell niche

A local tissue microenvironment that interacts with stem cells to maintain them and to regulate their cell fate. Stem cells divide relatively infrequently to generate transit-amplifying or progenitor cells, which divide rapidly and expand in numbers before generating more mature progeny.

Subgranular zone

(SGZ). A specific region of the hippocampus, defined as the thin layer at the border between the hippocampal granule cell layer and hilus.

Hippocampus

A brain structure that is important for the consolidation of short-term to long-term memory and spatial navigation.

Subventricular zone

(SVZ). Specialized layer in the developing or adult brain. In the adult SVZ, astrocytes are the stem cells which generate transit-amplifying or progenitor cells, which then differentiate into neuroblasts. Multi-ciliated ependymal cells line the walls of the lateral ventricle.

Paneth cells

One of the principal cell types of the intestinal epithelium, an important player in its defence against pathogenic microorganisms.

Dendritic spines

Dendrites are structures originating at the neuronal soma, which in some neurons can be highly complex, similar to a tree branch network. Dendrites receive impulses from other neurons through synapses, which are mainly located on spine-like protrusions of dendrites.

Tip cell

A specialized cell found at the leading edge of growing blood vessels, often displaying filopodia.

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Kania, A., Klein, R. Mechanisms of ephrin–Eph signalling in development, physiology and disease. Nat Rev Mol Cell Biol 17, 240–256 (2016). https://doi.org/10.1038/nrm.2015.16

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