Excitatory Eph receptors and adhesive ephrin ligands

doi:10.1016/S0955-0674(00)00197-6

Current Opinion in Cell Biology

Volume 13, Issue 2, 1 April 2001, Pages 196-203

https://doi.org/10.1016/S0955-0674(00)00197-6 Get rights and content

Abstract

Ephrins are cell surface associated ligands for Eph receptor tyrosine kinases and are implicated in repulsive axon guidance, cell migration, topographic mapping and angiogenesis. During the past year, Eph receptors have been shown to associate with glutamate receptors in excitatory neurons, suggesting a role in synapse formation or function. Moreover, ephrin/Eph signaling appears to regulate neural stem cell proliferation and migration in adult mouse brains. The mode of action of ephrin/Ephs has been expanded from repulsion to adhesion and from cell surface attachment to regulated cleavage.

Introduction

Eph receptor tyrosine kinases and their ligands, the ephrins, play crucial roles during development at the interface between pattern formation and morphogenesis — the process that generates tissues and organs [1]. Ephrins can be subdivided into two classes depending on the mode of cell surface attachment and their preference for subsets of Eph receptors. EphrinA ligands (ephrinA1–A5) are tethered to the cell surface by a glycosylphosphatidylinositol (GPI)-anchor and bind EphA receptors (EphA1–A8), whereas ephrinB ligands (ephrinB1–B3) are transmembrane proteins, which possess a cytoplasmic portion, and bind to EphB (EphB1–B6 and EphA4) receptors (reviewed in 2., 3.; see also [4]). Ephrins play important roles during axon guidance by providing a repulsive guidance signal to Eph receptor cells, that is a migrating growth cone expressing a particular Eph receptor would turn away from a cell that presents the cognate ephrin ligand. A characteristic of the ephrin–Eph signaling system is the ability to elicit bidirectional signaling, that is classical forward signaling by the Eph receptor via its intrinsic tyrosine kinase activity and reverse signaling by the transmembrane ephrinB ligand via its cytoplasmic domain (reviewed in 5., 6., 7.; see also Update). Ephrin functions in axon guidance, topographic map formation and angiogenesis have been covered by recent reviews 1., 3., 8., 9., 10., 11.. Here, I will review work on ephrins published over the course of the past year in the established fields of axon guidance and topographic map formation, and in new areas such as synaptogenesis and neural stem cell biology. I will also summarize progress on ephrin–Eph signaling, introducing novel concepts such as regulated cleavage and adhesion.

Section snippets

Ephrins and Ephs in retinocollicular mapping

Two important papers 12, 13 have shed new light on the role of ephrins in the formation of topographic maps in the visual system. Retinal ganglion cells (RGCs) send their axons to the appropriate area of the midbrain, termed the superior colliculus (SC) in mammals, such that their organization in the retina is preserved in the target. This allows the spatially intact projection of visual images to the brain. Earlier work had identified overlapping low-anterior to high-posterior gradients of

Axon guidance at the midline

Among the different choice points of navigating axons, the midline, which separates the left and right halves of the central nervous system, is particularly well studied and represents a rich source of attractive and repulsive guidance cues 17., 18., 19.. Axons of commissural neurons cross the midline and use attractive cues to navigate towards the ventral floorplate, a specialized structure at the ventral midline of the developing spinal cord. Longitudinally projecting axons may be guided

Neuromuscular development and topography

Earlier studies in rats and fish had implicated ephrin/Eph signaling in neuromuscular development by showing that spinal motor axon outgrowth into the periphery is influenced by somitic ephrins and that somitogenesis requires the interaction between segmentally expressed ephrins and Eph receptors 23., 24.. Targeted disruption of the ephA4 gene now provides genetic evidence for a critical role of this receptor in dorsoventral pathfinding of limb motor axons [25 radical dot ]. EphrinA ligands and their

Interaction of EphB receptors with NMDA receptors and regulation of synaptogenesis

Glutamate is the primary neurotransmitter at excitatory synapses in the central nervous system, and glutamate receptors of the NMDA type (N-methyl-d-aspartate) are implicated in synaptic plasticity processes [30]. A recent study [31 radical dot ] reports that the extracellular domains of the EphB2 receptor and the NR1 subunit of NMDA receptors interact in both heterologous cells and primary neurons. The association is specific for EphB2 (but not for EphA4) and NMDA-type glutamate receptors and is triggered

Ephrin/Eph signaling in subventricular zone neural stem cells

The subventricular zone (SVZ) of the lateral ventricles is the largest germinal zone of the adult brain. It contains neural stem cells that give rise to neuronal precursors (neuroblasts) which migrate to the olfactory bulbs. Little is known about the signals that regulate cell proliferation and migration in this region. A recent study [30] localized Eph receptors and ephrin ligands to the SVZ, including SVZ astrocytes; astrocytes represent the stem cells in this region. Disruption of ephrin/Eph

Regulated cleavage of ephrin ligands

During cell-to-cell communication, ephrin binding to Eph receptors causes cells to retract their processes or to migrate in opposite directions, despite the fact that ephrins and Ephs receptors form cell-attached, high-affinity multivalent complexes. A recent study [34 radical dot ] presented a mechanism that might explain how high-affinity binding could be terminated to allow cellular repulsion and axon withdrawal. When Hattori et al. [34] stimulate ephrinA2-expressing neuroblastoma cells with soluble

Alternative splicing of EphA7 turns repulsion into adhesion

In addition to its role in retinocollicular mapping, ephrinA5 was recently found to function in early neural tube closure, an observation that revealed an unusual signaling mechanism [35 radical dot ]. A small proportion (17%) of ephrinA5^−/− mutant mice have neural tube defects due to the failure of the neural folds to fuse at the dorsal midline. EphrinA5 and one of its cognate receptors EphA7 are coexpressed at the edges of the neural folds, suggesting that ephrin/Eph signaling may be important for this

Ephrin/Eph signaling

The activation of Eph receptors by ephrins follows rules previously established for other receptor tyrosine kinases: binding of the ligand causes receptor dimerization or reorientation, and the subsequent trans phosphorylation by the cytoplasmic kinase domains of the two receptors. Phosphorylation of specific tyrosine residues near the active loop of the catalytic domain regulates kinase activity, whereas phosphorylation of specific tyrosine residues outside the catalytic domain generates

Conclusions and perspectives

During the past year we have seen interesting novel concepts in ephrin/Eph biology and signaling. Ephrins not only regulate axon pathfinding and topographic mapping but also seem to be involved in later functions such as synapse formation, perhaps synapse function and neural stem cell proliferation and migration. Ephrins can be shed from the cell surface, allowing cells or their processes to detach from each other. Repulsion can be turned into adhesion by alternative splicing, permitting cells

Update

EphrinB2 and its cognate Eph receptors are important regulators of vascular morphogenesis 3., 9.. To separate ligand and receptor-like functions of ephrinB2 in mice, Adams et al. [49 radical dot ] replaced the endogenous gene by a ligand truncated in its carboxyl terminus (ephrinB2^ΔC). EphrinB2^ΔC/ΔC embryos showed defects in blood vessel formation very similar to those observed in ephrinB2^−/− animals. In contrast, the truncated ligand was sufficient to restore guidance of migrating cranial neural crest.

Acknowledgements

I thank I Grunwald, K Kullander, A Palmer, G Wilkinson and M Zimmer for suggestions on the manuscript and their ideas for figures. Work on ephrin and Eph in the author's laboratory is sponsored by grants from the Deutsche Forschungsgemeinschaft (DFG) and the Human Frontier Science Programme Organisation (HFSPO).

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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Ephrin-B2 is a candidate ligand for the Eph receptor, EphB6
FEBS Lett
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Control of cell behaviour by signalling through Eph receptors and ephrins
Curr Opin Neurobiol
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The distribution of ephrin-B1 and PNA-positive glycoconjugates is correlated with atypical melanoblast migration in Japanese Silky fowl embryos
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Citation Excerpt :
These include the cell-surface associated ephrin ligands, which signal through the Eph tyrosine kinase receptors. In general when Eph signaling is initiated, cells undergo a collapse response that inhibits their migration into ephrin-rich environments (Nakamoto, 2000; Klein, 2001; Krull, 2001; Gammill and Roffers-Agarwal, 2010). Eph receptors are expressed by neural crest cells, and Eph-receptor ligands are found in pathways that are avoided by the neural crest (Krull et al., 1997; Wang and Anderson, 1997; Santiago and Erickson, 2002; Kasemeier-Kulesa et al., 2006; Gammill and Roffers-Agarwal, 2010).
Melanoblasts are positively stimulated to migrate in the dorsolateral pathway of the avian embryo by ephrins, but are inhibited by PNA-binding glycoconjugates. We analyzed the potential role of these molecules in the Japanese Silky fowl, which displays intense internal pigmentation. The distribution of ephrin ligands was analyzed using Eph receptor-human Fc fusion proteins. Glycoconjugates were labeled using PNA-FITC. In Japanese Silky embryos, ventral areas, including the anterior- and posterior-half somites, expressed ephrin-B1 in a pattern that correlates with the atypical migratory pathways taken by Japanese Silky melanoblasts. White Leghorn embryos displayed little to no ephrin-Bs in the ventral paths. Conversely, PNA-binding barrier tissues, proposed to prevent melanoblasts from migrating ventrally in White Leghorn, are missing or have significant gaps in Japanese Silky embryos. Thus, studies of a naturally occurring pigmentation mutant confirm that a combination of cues regulates melanoblast migration in the chick embryo.
Ectodomain structures of Eph receptors
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Eph receptors, the largest subfamily of receptor tyrosine kinases (RTKs), and their ephrin ligands are important mediators of cell–cell communication that regulate axon guidance, long-term potentiation, and stem cell development, among others. By now, many Eph receptors and ephrins have also been found to play important roles in the progression of cancer. Since both the receptor and the ligand are membrane-bound, their interaction leads to the multimerization of both molecules to distinct clusters within their respective plasma membranes, resulting in the formation of discrete signaling centers. In addition, and unique to Eph receptors and ephrins, their interaction initiates bi-directional signaling cascades where information is transduced in the direction of both the receptor- and the ligand-bearing cells. The Ephs and the ephrins are divided into two subclasses, A and B, based on their affinities for each other and on sequence conservation. Crystal structures and other biophysical studies have indicated that isolated extracellular Eph and ephrin domains initially form high-affinity heterodimers around a hydrophobic loop of the ligand that is buried in a hydrophobic pocket on the surface of the receptor. The dimers can then further arrange by weaker interactions into higher-order Eph/ephrin clusters observed in vivo at the sites of cell–cell contact. Although the hetero-dimerization is a universal way to initiate signaling, other extracellular domains of Ephs are involved in the formation of higher-order clusters. The structures also show important differences defining the unique partner preferences of the two ligand and receptor subclasses, namely, how subclass specificity is determined both by individual interacting residues and by the precise architectural arrangement of ligands and receptors within the complexes.
Global expression analysis identified a preferentially nerve growth factor-induced transcriptional program regulated by sustained mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and AP-1 protein activation during PC12 cell differentiation
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In addition, several other preferentially NGF-induced genes (Mmp3, Mmp10, Plk2, and Rgs2) have previously been shown to be critical for PC12 differentiation through siRNA knockdown or functional inhibition (36–38). Many also have established roles in neuronal or brain differentiation/function (Sgk, Sprr1a, Jmjd3, Kctd11, Ifrd1, Epha2, rno-miR-21, Pai1, Tph1, Sema6a, Hbegf, Egr3, Arc, Vgf, Dclk1) (21, 39–55). In total, at least 21 (30%) of the preferentially NGF-induced genes have previously described roles in neuronal differentiation/function in PC12 cells and other neuronal systems.
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Several synaptically localized adhesion molecules are potentially capable of mediating these interactions, including neural cell adhesion molecules (NCAMs), L1 cell-adhesion molecule (CD171), syndecan 2 and 4, ephrinB2, ephrin B2 receptor (EphB2), integrins and β-catenin. TGF-β members have been shown to regulate cell adhesion molecules in multiple cellular contexts [30–41]. Hence, TGF-β members might be candidate signaling molecules for orchestrating important aspects of synaptogenesis in the developing and adult brain.
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ReviewExcitatory Eph receptors and adhesive ephrin ligands

Abstract

Introduction

Section snippets

Ephrins and Ephs in retinocollicular mapping

Axon guidance at the midline

Neuromuscular development and topography

Interaction of EphB receptors with NMDA receptors and regulation of synaptogenesis

Ephrin/Eph signaling in subventricular zone neural stem cells

Regulated cleavage of ephrin ligands

Alternative splicing of EphA7 turns repulsion into adhesion

Ephrin/Eph signaling

Conclusions and perspectives

Update

Acknowledgements

References and recommended reading

Int Rev Cytol

FEBS Lett

Curr Opin Neurobiol

Curr Opin Neurobiol

Curr Opin Neurobiol

Curr Biol

Curr Opin Biotechnol

Curr Opin Neurobiol

Neuron

Cell

Neuron

Neuron

Curr Biol

Neuron

Neuron

Neuron

Neuron

Neuron

Mol Cell Neurosci

Cell

Cell

Eph receptors and ephrins: effectors of morphogenesis

Development

The ephrins and Eph receptors in neural development

Annu Rev Neurosci

Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development

Genes Dev

Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina

Development

Axon guidance at the central nervous system midline

Cell Mol Life Sci

Review
Excitatory Eph receptors and adhesive ephrin ligands