Ephrin signalling controls brain size by regulating apoptosis of neural progenitors.
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.
Depaepe
Vanessa
V
Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), University of Brussels, Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.
Suarez-Gonzalez
Nathalie
N
Dufour
Audrey
A
Passante
Lara
L
Gorski
Jessica A
JA
Jones
Kevin R
KR
Ledent
Catherine
C
Vanderhaeghen
Pierre
P
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
D036386:Ephrin-A5; D036342:Ephrins; D036081:Receptors, Eph Family; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases