Multiple roles of eph receptors and ephrins in neural development

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Abstract
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.