"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.
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