1. Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), University of Brussels, Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium
2. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA

Correspondence to: Pierre Vanderhaeghen¹ Correspondence and requests for materials should be addressed to P.V. (Email: pvdhaegh@ulb.ac.be).

Abstract

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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