A dual role of EphB1/ephrin-B3 reverse signaling on migrating striatal and cortical neurons originating in the preoptic area: should I stay or go away?

Abstract

During embryonic development the preoptic area (POA) gives rise to two populations of neurons which are generated at the same time, cortical interneurons and striatal cells. POA-derived cortical interneurons take a superficial path and avoid the developing striatum (Str) when they migrate to their target region. We found that EphB1, which is expressed in the striatal anlage, prevents cortical interneurons from entering the Str via ephrin-B3 reverse signaling. In contrast, for striatal neurons which also express ephrin-B3, EphB1 acts as a stop signal. This dual role of EphB1 is due to differences in ephrin-B3 reverse signaling cascades. For striatal neurons, binding of EphB1 to ephrin-B3 reduces endogenously high levels of pSrc and pFAK, which then causes the cells to stop migration. In contrast, in cortical interneurons EphB1-ephrin-B3 reverse signaling leads to phosphorylation of Src and focal adhesion kinase (FAK) which then mediates repulsion. Consistent with these in vitro findings, in an ephrin-B3 knockout mouse line, we discovered misrouted cortical interneurons in the Str and an over-migration of striatal neurons in their target region. Thus, EphB1/ephrin-B3 reverse signaling has a different impact on two sets of neurons which are generated at the same time and place: it can act as a repulsive cue for migrating neurons or it can terminate neuronal migration, a novel role of the Eph/ephrin system.

Autonomous and non-autonomous roles for ephrin-B in interneuron migration

“…Candidate Eph receptors expressed in inhibitory interneurons include EphB1, EphB2, EphB3, EphB6, and EphA4 (Fig. S5 and Data File S1) (Rudolph et al, 2014; Villar-Cervino et al, 2015; Zimmer et al, 2011). Moreover, in recent experiments, we find that EphB1 −/− protein-null knockouts (Williams et al, 2003) and EphB1 T-lacZ/T-lacZ mutants which truncate the EphB1 intracellular kinase domain (Chenaux and Henkemeyer, 2011) both selectively exhibit a reduced population of GAD65-GFP interneurons without any reductions in the GAD67-GFP group (unpublished data).…”

“…Previous reports of ephrin-B involvement in interneuron migration centered only on ephrin-B3 and mainly relied on in vitro experiments and only analyzed one embryonic time point (E14) showing a very mild phenotype at best without any analysis of adult populations (Rudolph et al, 2014; Zimmer et al, 2011). Our in depth in vivo analysis indicates ephrin-B3 alone has little if any effect on interneuron migration as we failed to notice any consistent abnormality in the EB3 single mutants in embryos using either GAD67-GFP or GAD65-GFP reporters.…”

Intramembranous processing by γ‐secretase regulates reverse signaling of ephrin‐B2 in migration of microglia

“…Reverse signaling of ephrin-B proteins has been found to induce cell repulsion, cytoskeletal reorganization and disassembly of FAS in many cell types (Foo et al 2006;Rudolph et al 2014;Tanaka et al 2003). As mentioned above, cell types that rely on high motility, like macrophages, invasive cancer cells and dendritic cells, often form podosomes instead of FAS.…”

Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice

“…In contrast, the failure of POA-derived cells to migrate into the cortex was surprising. The POA gives rise to a separate set of cortical interneurons (Gelman et al 2009), which may rely on different guidance cues than cells from the MGE and CGE (Rudolph et al 2014;Zimmer et al 2011).…”