Axon Guidance and Neural Development

The Eph family of receptor tyrosine kinases and their associated ephrin ligands play a central role in neural development by providing repulsive guidance cues that direct axonal targeting. Specifically, a migrating growth cone expressing a given Eph receptor will turn away from cells expressing cognate ephrin ligands, as a result of the disassembly or redistribution of filamentous actin networks at the leading edge [44]. Two classes of ephrins are defined on the basis of their mode of cell surface attachment. The ephrin A ligands utilize a glycophosphatidylinositol (GPI) linkage for cell-surface attachment and bind the EphA receptors, while ephrinB ligands are transmembrane proteins that bind EphB receptors.

Recent structural characterization of the ephrin-B2/EphB2 receptor complex provides new insights into the potential signaling mechanisms utilized (Fig. 5) [45]. This structure provides details of the receptor-ligand binding site and of a "circular" 2:2 receptor-ligand complex that is thought to be relevant to signaling. The organization observed in the crystal structure is consistent with ligand-induced clustering of the EphB2 receptor, resulting in the trans-autophosphorylation required for activation and subsequent recruitment of signaling molecules, including src family kinases and GTP-activating proteins (GAPS) [46]. Engagement also results in clustering of the ephrin ligand, providing another example of bidirectional signaling, as the cytoplasmic domain of ephrin-B2 is required for normal angiogenesis and vascular morphogenesis [46]. Furthermore, consistent with the propensity to form higher order oligomers, the crystal structure suggests the formation of an extended two-dimensional signaling complex (super-cluster) of receptors and ligands at the cell-cell interface (in contrast to the one-dimensional array proposed for the CTLA-4/B7 complexes), which might afford enhanced signaling.

The proposed long-range organization suggests that, in addition to a direct role in signaling, engagement of the Eph

Figure 5 Structure of the ephrin-B2/EphB2 receptor complex. (A) Circular tetramer formed by the interaction of two EphB2 receptors (green) with two ephrinB2 ligands (yellow) thought to represent the favored receptor-ligand organization in vivo. Note that each ligand contacts two receptor molecules, but there are no ligand-ligand or receptor-receptor contacts. (B) Crystal packing results in another tetramer (elliptical), in which an extensive interface is formed between two receptor molecules. The physiological relevance of this binding interaction remains to be proven but may be consistent with the propensity of Eph/ephrin molecules to form higher order oligomers. (C) A "layer" from the ephrin-B2/EphB2 receptor complex crystal structure showing the long-range, two-dimensional ordered array formed by the combination of both the circular (highlighted in red) and elliptical (highlighted in blue) tetramers. Such an organized network could potentially play roles in signaling and/or adhesion.

Figure 5 Structure of the ephrin-B2/EphB2 receptor complex. (A) Circular tetramer formed by the interaction of two EphB2 receptors (green) with two ephrinB2 ligands (yellow) thought to represent the favored receptor-ligand organization in vivo. Note that each ligand contacts two receptor molecules, but there are no ligand-ligand or receptor-receptor contacts. (B) Crystal packing results in another tetramer (elliptical), in which an extensive interface is formed between two receptor molecules. The physiological relevance of this binding interaction remains to be proven but may be consistent with the propensity of Eph/ephrin molecules to form higher order oligomers. (C) A "layer" from the ephrin-B2/EphB2 receptor complex crystal structure showing the long-range, two-dimensional ordered array formed by the combination of both the circular (highlighted in red) and elliptical (highlighted in blue) tetramers. Such an organized network could potentially play roles in signaling and/or adhesion.

receptor-ligand pairs may also provide essential adhesive functions. The first evidence supporting this notion came from the observation that ~17% of mice defective in ephrinA5 exhibit neural tube defects, which is not consistent with the classical repulsive effects attributed to ephrin/Eph receptor function [48]. These studies also revealed that the expression of splice variants of an ephrinA5 receptor (i.e., EphA7) which lack the intracellular kinase domain support direct adhesive interactions with ephrinA5-expressing cells48. This provides yet another example of the close linkage between signaling and adhesive interactions.

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