Editors' ChoiceReceptor signaling

A Surprising Partner

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Science Signaling  16 Sep 2008:
Vol. 1, Issue 37, pp. ec327
DOI: 10.1126/scisignal.137ec327

Interactions between ephrin-As and EphA receptor tyrosine kinases on adjoining cells can lead not only to “forward signaling” through EphA but also to “reverse signaling” into ephrin-A-bearing cells. Because ephrin-As are anchored to the cell membrane through glycosylphosphatidylinositol (GPI) linkages, they must associate with transmembrane proteins to activate such an intracellular reverse signal. Noting that, like ephrin-As, the p75 neurotrophin receptor is found in membrane caveolae of developing retinal ganglion cells (RGCs), Lim et al. explored the hypothesis that p75 interacts with ephrin-As to mediate repulsive signals implicated in RGC retinotopic mapping in the superior colliculus. Immunostaining revealed that, midway through development of the SC retinotopic map, ephrin-A5 and ephrin-A2 were expressed in RGCs (in a gradient across the retina) and their axons and that EphA receptors were expressed in a graded fashion in the superior colliculus. p75 was present in RGCs and their axons and, in primary cultures of mouse retina, often colocalized with ephrin-A5 and ephrin-A2. Ephrin-A2 coimmunoprecipitated with p75 from retinal tissue, as well as from PC12 cells transfected with ephrin-A2 and 293 cells transfected with both p75 and ephrin-A2 or ephrin-A5. EphA7 bound to ephrin-As but not p75 in transfected 293 cells and stimulated the phosphorylation of caveolar Fyn only when ephrin-A and p75 were both present. Whereas axons from wild-type retinal explants preferentially avoided a substrate containing EphA7, axons from p75 knockout mice showed no such preference. Analysis of retinotopic mapping in the SC of mice lacking p75 and mice in which p75 was knocked out in retina revealed an anterior shift in the termination zones of RGCs, a change consistent with decreased repulsive signaling. The authors thus propose that p75—classically thought to act as a neurotrophin receptor—interacts with ephrin-As to mediate reverse signaling.

Y.-S. Lim, T. McLaughlin, T.-C. Sung, A. Santiago, K.-F. Lee, D. D. M. O'Leary, p75NTR mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 59, 746-758 (2008). [PubMed]

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