, 2005); thus, in general, the two modes of Eph and ephrin intera

, 2005); thus, in general, the two modes of Eph and ephrin interaction outlined in our model do not appear to require axon-axon interaction. However, it is still worth considering whether

repulsive forward signaling from, for example, ephrinAs on medial LMC axons to EphAs on lateral axons might contribute to their segregation prior to entry into the limb mesenchyme ( Lance-Jones and Landmesser, 1981a). Our data suggest that Ephs and ephrins reside in three types of microdomains or patches in LMC neuron growth cones: (1) Eph only or (2) ephrin only microdomains in growth cones expressing low levels Tyrosine Kinase Inhibitor Library of ephrins and (3) microdomains containing both Ephs and ephrins in growth cones expressing high levels of ephrins. Our observation that a knockdown of ephrin leads to a redistribution of Ephs and ephrins to Eph- or ephrin-exclusive

patches suggests that ephrin protein expression levels control the relocalization of Ephs and ephrins, which in turn shifts the balance between cis-attenuation and parallel trans-signaling. Although the detailed mechanism of how ephrin levels mediate Eph/ephrin redistribution remains to be clarified, when compared with the compacted and highly ordered Eph-ephrin complex assembled to generate a trans-signaling center, Ephs are loosely packed in the absence of trans-interaction ( Brückner et al., 1999), and thus are possibly more susceptible to cis-binding by ephrins. Regardless of which Eph protein domains are bound by ephrins in cis, the attenuation of ephrin:Eph forward signaling might be caused by intercalation selleck chemical of ephrins

into Eph domains, leading to diminished degree of Eph receptor clustering, an event essential for downstream signaling ( Egea et al., 2005). Similarly, our observation that some neurons express high levels of ephrins, possibly in excess and therefore unbound to Ephs in cis, also raises the question of whether such free ephrins might elicit attractive reverse signaling in response to EphAs provided in trans. In medial LMC neuron growth cones expressing high levels of ephrin-As, we fail to find any obvious ephrin-A-only isothipendyl microdomains or attractive ephrin-A reverse signaling. This suggests that in these neurons, free ephrin-As might be dispersed throughout the cell surface without compact clustering that is prerequisite for reverse signaling in response to EphAs in trans ( Palmer et al., 2002). In order to terminate signaling or to allow subsequent signaling events, the Eph-ephrin complexes can be removed from the cell surface by endocytosis (Marston et al., 2003 and Zimmer et al., 2003) implicating ephrin cleavage (Hattori et al., 2000 and Janes et al., 2005). Our observation indicating Eph and ephrin cis-interactions raise the question of whether microdomains containing both Ephs and ephrins reside on the cell surface or whether they are present intracellularly.

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