Brain-Region Specific Apoptosis Triggered by Eph/ephrin Signaling

Abstract

Eph receptors and their ligands, ephrins, are abundantly expressed in neuroepithelial cells of the early embryonic brain. Overstimulation of Eph signaling in vivo increases apoptotic cell death of neuroepithelial cells, whereas null mutation of the Eph gene leads to the development of a larger brain during embryogenesis. Thus, it appears that Eph-ephrin signaling plays a role in regulating apoptotic cell death of neuroepithelial cells, thereby influencing brain size during embryonic development. Interestingly, Eph-ephrin signaling is bi-directional, with forward signaling from ephrin- to Eph-expressing cells and reverse signaling from Eph- to ephrin-expressing cells. However, it is not clear whether this forward or reverse signaling plays a role in regulating the size of the neuroepithelial cell population during early brain development. Also, Eph receptors and their corresponding ligands are mutually exclusive in their expression domains, and they encounter each other only at interfaces between their expression domains. This expression pattern may be a critical mechanism for preventing overstimulation of Eph-ephrin signaling. Nevertheless, Eph receptors are co-expressed with their corresponding ligands in certain brain regions. Recently, two studies demonstrated that brain region-specific apoptosis may be triggered by the overlapping expression of Eph and ephrin, a theme that will be explored in this mini-review.

EphA Receptors Form a Complex with Caspase-8 to Induce Apoptotic Cell Death

“…Although it was postulated that fusion of neural folds at the midline is mediated by an adhesive interaction between EphA7 and ephrin-A5, an alternative explanation is that a significant increase in the dorsal midline cell population may be responsible for the neural tube closure defects in ephrin-A5 null mutant embryos. Consistent with this hypothesis, recent studies using in vivo expression of ephrinA5-Fc or EphA8-Fc revealed that upregulation of Eph/ephrin signaling in the dorsal midline play a causative role in triggering massive apoptotic cell death ( Kim et al, 2013 ; Park et al, 2013 ). These findings suggest that cell-cell contact in a brain region where Eph and ephrin are co-expressed triggers the pro-apoptotic signaling pathway downstream of the Eph-ephrin complex, a critical mechanism for modulating the size of the neuroepithelial cell population or remodeling brain tissue ( Park, 2013 ).…”

“…Consistent with this hypothesis, recent studies using in vivo expression of ephrinA5-Fc or EphA8-Fc revealed that upregulation of Eph/ephrin signaling in the dorsal midline play a causative role in triggering massive apoptotic cell death ( Kim et al, 2013 ; Park et al, 2013 ). These findings suggest that cell-cell contact in a brain region where Eph and ephrin are co-expressed triggers the pro-apoptotic signaling pathway downstream of the Eph-ephrin complex, a critical mechanism for modulating the size of the neuroepithelial cell population or remodeling brain tissue ( Park, 2013 ). Although the pro-apoptotic pathway downstream of the Eph/ephrin complex has not been clearly elucidated, a recent study suggested that EphA receptors may cross-talk with cell death receptors such as tumor necrosis factor receptor 1 (TNFR1) ( Lee et al, 2013 ).…”

“…The EphA7-mediated signaling pathway has been implicated in triggering apoptotic cell death during early brain development ( Depaepe et al, 2005 ; Kim et al, 2013 ; Park et al, 2013 ). To explore the potential mechanism underlying the apoptotic signaling pathway downstream of EphA7, we investigated whether EphA7 can form a complex with caspase-8 in intact cells.…”

“…Early apoptotic cell death in neuroepithelial cells in the developing brain has been implicated in regulating mammalian brain size ( Kuan et al, 2000 ). One class of proteins implicated in apoptotic neuroepithelial cell death is Eph receptors and their ligands, ephrins, which are abundantly expressed during early brain development ( Park, 2013 ). The first evidence that Eph/ephrin signaling triggers apoptosis came from an ectopic ephrin-A5 expression study in EphA7-expressing brain tissue, where massive apoptosis and a subsequent decrease in cortical size was observed as a result of Eph and ephrin co-expression ( Depaepe et al, 2005 ).…”

Identification of the 187 bp EphA7 Genomic DNA as the Dorsal Midline-Specific Enhancer of the Diencephalon and Mesencephalon

“…Expression studies using Eph-Fc or ephrin-Fc fusion proteins reveal that the developing embryo is subdivided into domains demarcated by reciprocal and mutually exclusive expressions of Eph receptors and its corresponding ligands and ephrins ( Gale et al, 1996 ; Park, 2013 ; Park et al, 2013 ). For example, EphA receptors are predominantly expressed in the dorsal region of the diencephalon and anterior mesencephalon, whereas ephrin-A ligands express in the posterior mesencephalon.…”