title: Ephrin signalling controls brain size by regulating apoptosis of neural progenitors.
abstract: Mechanisms controlling brain size include the regulation of neural progenitor cell proliferation, differentiation, survival and migration. 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.
authors.affiliation: Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), University of Brussels, Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Depaepe
authors.forename: Nathalie
authors.initials: N
authors.lastname: Suarez-Gonzalez
authors.forename: Audrey
authors.initials: A
authors.lastname: Dufour
authors.forename: Lara
authors.initials: L
authors.lastname: Passante
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Gorski
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Jones
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanderhaeghen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D036386:Ephrin-A5 / Q000235:genetics / Q000378:metabolism; D036342:Ephrins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009929:Organ Size; D036081:Receptors, Eph Family / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D036386:Ephrin-A5; D036342:Ephrins; D036081:Receptors, Eph Family; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases