"Reverse" signaling is one unique property of ephrin ligands that allows for the transmission of an intracellular signal in ephrin-expressing cells that is distinct from the signal transmitted in Eph receptor-expressing cells. Although the mechanism of "reverse" signaling by ephrin-As is not well understood, it is relatively surprising considering that ephrin-A ligands are attached to the cell membrane solely by a GPI linkage and unlike ephrin-Bs, lack a potential intracellular signaling domain. Nonetheless, certain ephrin-A ligands are known to initiate reverse signaling cascades like ephrin-A5, which has been shown to stimulate the spreading of growth cones in cultures of mouse spinal motor neurons. Interestingly, reverse signaling by ephrin-A5 was demonstrated to be GPI-dependent as the elimination of all GPI linkages by the application of a phosphatidlyinositol-specific phospholipase C abolished the positive effects of ephrin-A5 on growth cone spreading. Additionally, EphA receptors were shown to exert opposite effects on motor neuron growth cones by reducing growth cone size.
This finding that ephrin-A5 promotes growth cone survival that is opposite of EphA signaling and mediated directly by ephrin-A5 reverse signaling has important implications for axon guidance as it provides a mechanism by which migrating axons expressing EphAs would preferentially avoid ephrin-A5 expressing cells and possibly migrate towards cells with lower expression of ephrin-A5. This mechanism is in fact the same one that mediates the guidance of retinal ganglion cells to distinct regions in the superior colliculus during the formation of the retinotopic map. High ephrin-A5 expression on cells in the posterior region of the SC bind to EphAs expressed in RGCs migrating from the temporal retina, inducing growth cone collapse and repelling these RGCs away from the posterior SC towards a region of low ephrin-A5 expression in the anterior SC.
^Cerretti DP, Copeland NG, Gilbert DJ, Jenkins NA, Kuefer MU, Valentine V, Shapiro DN, Cui X, Morris SW (Sep 1996). "The gene encoding LERK-7 (EPLG7, Epl7), a ligand for the Eph-related receptor tyrosine kinases, maps to human chromosome 5 at band q21 and to mouse chromosome 17". Genomics35 (2): 376–9. doi:10.1006/geno.1996.0371. PMID8661153.
^Kozlosky CJ, VandenBos T, Park L, Cerretti DP, Carpenter MK (Oct 1997). "LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain". Cytokine9 (8): 540–9. doi:10.1006/cyto.1997.0199. PMID9245480.
^Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M, Nikolov DB (May 2004). "Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling". Nat. Neurosci.7 (5): 501–9. doi:10.1038/nn1237. PMID15107857.
^ abMarquardt T, Shirasaki R, Ghosh S, Andrews SE, Carter N, Hunter T, Pfaff SL (April 2005). "Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains". Cell121 (1): 127–39. doi:10.1016/j.cell.2005.01.020. PMID15820684.
^Drescher U, Kremoser C, Handwerker C, Löschinger J, Noda M, Bonhoeffer F (August 1995). "In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases". Cell82 (3): 359–70. doi:10.1016/0092-8674(95)90425-5. PMID7634326.
Wilkinson DG (2001). "Multiple roles of EPH receptors and ephrins in neural development". Nat. Rev. Neurosci.2 (3): 155–64. doi:10.1038/35058515. PMID11256076.
Winslow JW, Moran P, Valverde J, et al. (1995). "Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation". Neuron14 (5): 973–81. doi:10.1016/0896-6273(95)90335-6. PMID7748564.
Gale NW, Holland SJ, Valenzuela DM, et al. (1996). "Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis". Neuron17 (1): 9–19. doi:10.1016/S0896-6273(00)80276-7. PMID8755474.
Lackmann M, Mann RJ, Kravets L, et al. (1997). "Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor". J. Biol. Chem.272 (26): 16521–30. doi:10.1074/jbc.272.26.16521. PMID9195962.
Ciossek T, Monschau B, Kremoser C, et al. (1998). "Eph receptor-ligand interactions are necessary for guidance of retinal ganglion cell axons in vitro". Eur. J. Neurosci.10 (5): 1574–80. doi:10.1046/j.1460-9568.1998.00180.x. PMID9751130.
Janis LS, Cassidy RM, Kromer LF (1999). "Ephrin-A binding and EphA receptor expression delineate the matrix compartment of the striatum". J. Neurosci.19 (12): 4962–71. PMID10366629.
Gerlai R, Shinsky N, Shih A, et al. (1999). "Regulation of learning by EphA receptors: a protein targeting study". J. Neurosci.19 (21): 9538–49. PMID10531456.