Ephrin signalling controls brain size by regulating apoptosis of neural progenitors.
Depaepe, Vanessa 1; Suarez-Gonzalez, Nathalie 1; Dufour, Audrey 1; Passante, Lara 1; Gorski, Jessica A 2; Jones, Kevin R. 2; Ledent, Catherine 1; Vanderhaeghen, Pierre 1
[Letter]
Nature.
435(7046):1244-1250, June 30, 2005.
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Mechanisms controlling brain size include the regulation of neural progenitor cell proliferation, differentiation, survival and migration 1,2. Here we show that ephrin-A/EphA receptor signalling plays a key role in controlling the size of the mouse cerebral cortex by regulating cortical progenitor cell apoptosis. In vivo gain of EphA receptor function, achieved through ectopic expression of ephrin-A5 in early cortical progenitors expressing EphA7, caused a transient wave of neural progenitor cell apoptosis, resulting in premature depletion of progenitors and a subsequent dramatic decrease in cortical size. In vitro treatment with soluble ephrin-A ligands similarly induced the rapid death of cultured dissociated cortical progenitors in a caspase-3-dependent manner, thereby confirming a direct effect of ephrin/Eph signalling on apoptotic cascades. Conversely, in vivo loss of EphA function, achieved through EphA7 gene disruption, caused a reduction in apoptosis occurring normally in forebrain neural progenitors, resulting in an increase in cortical size and, in extreme cases, exencephalic forebrain overgrowth. Together, these results identify ephrin/Eph signalling as a physiological trigger for apoptosis that can alter brain size and shape by regulating the number of neural progenitors.
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