The Ephrin-A5/EphA4 Interaction Modulates Neurogenesis and Angiogenesis by the p-Akt and p-ERK Pathways in a Mouse Model of TLE

Abstract

Studies have shown that neurogenesis and angiogenesis do exist in temporal lobe epilepsy (TLE). The ephrin ligands and Eph receptors are the largest members of receptor tyrosine kinases, and their interaction via cell-cell contact participates in cell proliferation, differentiation, migration, and tissue remodeling. However, there is little information about the function of the ephrin-A5/EphA4 complex in TLE. In the current study, we found that ephrin-A5 was expressed in astrocytes, while EphA4 existed in endothelial cells in the hippocampus in a mouse model of TLE. Furthermore, the messenger RNA (mRNA) and protein levels of both ephrin-A5 and EphA4 and the binding capacity of ephrin-A5/EphA4 showed gradual increase in spatiotemporal course. When ephrin-A5-Fc was injected into the hippocampus at 3 days post-status epilepticus (SE) for 7 days, the spontaneous recurrent seizure (SRS) frequency and intensity of the mice attenuated in the following 2 weeks. Furthermore, doublecortin-positive neuronal progenitor cells were reduced in the subgranular zone, and the density of microvessels decreased in the hilus. The molecular mechanism was attributed to ephrin-A5-Fc-induced inhibition of phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt), and also EphA4 and VEGF reduction. In summary, interaction between ephrin-A5 and EphA4 could mediate the ERK and Akt signaling pathways in pilocarpine-induced epilepsy, and intervention of the ephrin/Eph interaction may play an essential role in the suppression of newborn neuron generation, microvessel remodeling, and SRS in a mouse model of TLE. The ephrin-A5/EphA4 communication may provide a potential therapy for the treatment of TLE.

EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro

“…Eph tyrosine kinase receptors and their ephrin ligands have been identified as important regulators of neural stem/progenitor cells differentiation [13, 16, 44-46]. In a prior study, Katakowski et al reported that EphB2 promotes a neuronal fate in adult subventricular neural precursor cells [19].…”

Decreased maternal behavior and anxiety in ephrin‐A5−/− mice

“…Thus, it is possible that the decreased maternal behavior seen in the null mice is due to alteration in the mesolimbic DA system. However, since ephrin-A5 is expressed broadly in the brain (Deschamps et al , 2009, Gao et al , 1998), and has been shown to regulate neurogenesis (Depaepe et al , 2005, Gerstmann et al , 2015, Noh & Park, 2015, Shu et al , 2016), and formation of several other neural circuits (Carvalho et al , 2006, Guellmar et al , 2009, Steinecke et al , 2014, Tadesse et al , 2013, Yates et al , 2014) the precise mechanism underlying maternal care deficiency remains to be determined by future investigations. Thus, the mechanistic connection of ephrin-A5 function to maternal behavior is at present unclear, and this gene may not regulate maternal care exclusively.…”

Multimodal Eph/Ephrin signaling controls several phases of urogenital development

“…18,19 Figure 3 | (Continued) ED 11 (XY, YZ bottom, XZ left; dashed lines indicate positioning of planes; dorsal and caudal orientation is indicated by arrows in XY planes). EphA4 is expressed in the periureteric mesenchyme, sheeting the WD, CND, and MM and also in the cells of the induced UB (asterisk in j,k).…”

“…CND regression critically depends on retinoic acid and Ret signaling. 7-9,31 ERK is a downstream target of Ret and Eph/Ephrin signaling, [18][19][20] and inhibition of ERK led to failure in UB formation and CND aplasia. 31 Our analysis at ED 11.5 localized high ERK1/2 activation in the UGS and the caudal CND with a gradual decrease toward the UB.…”