Expression of EphA8-Fc in transgenic mouse embryos induces apoptosis of neural epithelial cells during brain development

EphAs and ephrin-As are expressed in multiple regions of the developing brain and have been implicated in regulating brain size. Here, we report the identification of a novel mechanism in which reverse signaling through ephrin-As controls neural epithelial cell number in the developing brain. Ectopic expression of EphA8-Fc in transgenic embryos induced apoptosis of neural epithelial cells, which was accompanied by a dramatic decrease in brain size. The number of ephrin-A5-expressing cells was significantly reduced in the brain region where EphA8-Fc was ectopically expressed. Furthermore, in vitro culture of the dissociated neuroepithelial cells revealed that EphA8-Fc enhanced apoptotic cell death of the ephrinA5-expressing cells in a caspase-dependent manner. Thus, our results suggest that reverse signaling through ephrin-As is biochemically linked with caspase-dependent proapoptotic signaling during early brain development. (c) 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 702-712, 2013