EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence

Abstract

Inhibitory interneurons control the flow of information and synchronization in the cerebral cortex at the circuit level. During embryonic development, multiple subtypes of cortical interneurons are generated in different regions of the ventral telencephalon, such as the medial and caudal ganglionic eminence (MGE and CGE), as well as the preoptic area (POA). These neurons then migrate over long distances towards their cortical target areas. Diverse families of diffusible and cell-bound signaling molecules, including the Eph/ephrin system, regulate and orchestrate interneuron migration. Ephrin A3 and A5, for instance, are expressed at the borders of the pathway of MGE-derived interneurons and prevent these cells from entering inappropriate regions via EphA4 forward signaling. We found that MGE-derived interneurons, in addition to EphA4, also express ephrin A and B ligands, suggesting Eph/ephrin forward and reverse signaling in the same cell. In vitro and in vivo approaches showed that EphA4-induced reverse signaling in MGE-derived interneurons promotes their migration and that this effect is mediated by ephrin A2 ligands. In EphA4 mutant mice, as well as after ephrin A2 knockdown using in utero electroporation, we found delayed interneuron migration at embryonic stages. Thus, besides functions in guiding MGE-derived interneurons to the cortex through forward signaling, here we describe a novel role of the ephrins in driving these neurons to their target via reverse signaling.

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.…”

Axon guidance in the auditory system: Multiple functions of Eph receptors

“…Eph proteins regulate areal specification of cortex and guidance of thalamocortical axons to the appropriate cortical areas (Dufour et al, 2003, Robichaux et al, 2014). They influence cortical cell migration (Steinecke et al, 2014), laminar specification (Mann et al, 2002), topography (Cang et al, 2008a), and columnar organization (Torii et al, 2009, Dimidschstein et al, 2013). In primary auditory cortex, null mutations in EphB2 and EphB3 result in degraded frequency selectivity (Intskirveli et al, 2011).…”

Effect of EphA7 Silencing on Proliferation, Invasion and Apoptosis in Human Laryngeal Cancer Cell Lines Hep-2 and AMC-HN-8

“…The erythropoietin-producing hepatoma-amplified sequence (Eph) receptors are a large family of receptor tyrosine kinases comprising eight EphA and six EphB receptors in humans [5]. Recent studies unveiled the involvement of Eph-ephrin interaction in a variety of developmental processes including arterial-venous differentiation [6], cell migration [7] which results in compartmentalizing cell subpopulations in the developing tissue, and cell movement into the appropriate embryonic environment which may determine a particular cell fate and result in cell differentiation and patterning. Besides such physiological roles, recent studies have also demonstrated that many human malignancies are involved in dysregulated expression of Eph receptors, including up-regulation of ephrin-A1 or -B2 in melanoma [8], up-regulation of EphB2 in stomach cancer [9,10] and in breast cancer [11], and up-regulation of EphA2 in prostate [12], breast [13], and esophageal cancers [14], some of which were shown to be associated with tumor invasion or tumor metastasis and therefore associated with poor prognosis.…”