Ephrin A5 is aprotein that in humans is encoded by theEFNA5gene.[5][6][7]
Ephrin A5 is aglycosylphosphatidylinositol (GPI)-anchored protein of the ephrin-A subclass ofephrin ligands that binds to the EphA subclass ofEph receptors. Ephrin A5 has also been shown to bind to theEphB2 receptor.[8]
"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 thecell 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 ofgrowth cones in cultures of mouse spinalmotor neurons.[9] Reverse signaling by ephrin A5 was demonstrated to be GPI-dependent as the elimination of all GPI linkages by the application of a phosphatidlyinositol-specificphospholipase 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 foraxon 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.[9] This mechanism is in fact the same one that mediates the guidance ofretinal ganglion cells to distinct regions in thesuperior colliculus during the formation of theretinotopic map. High ephrin A5 expression on cells in theposterior 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 theanterior SC.[10]
