Abstract
Mechanisms controlling brain size include the regulation of neural progenitor cell proliferation, differentiation, survival and migration1,2. 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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Acknowledgements
We thank G. Vassart for continuous support and interest, and members of IRIBHM for help and advice, in particular D. Communi, N. Gaspard, M.-A. Lambot, S. Pietri, J. Seibt and F. Pauwels. We also thank the Development Studies Hybridoma Bank; T. Ciossek for sharing the EphA7 mutant mice; C. d'Enfert and J.-M. Ghigo for the gift of the pKOBEGA plasmid; A. de Kerchove for discussions about BAC recombineering; A. Deplano for help with pulse-field electrophoresis; S. Tajbakhsh for the gift of the floxed eGFP cassette; F. Stewart for the gift of the frt-Neo cassette and the 294-Flp bacteria; A. Goffinet for the gift of mouse reelin plasmid; R. Hevner for the gift of Tbr1 antibody; and F. Polleux for critically reading the manuscript. This work was funded by grants from the Belgian Funds for Scientific Research (FNRS and FRSM), the Belgian Queen Elizabeth Medical Foundation, the Belgian Interuniversity Attraction Poles Programme (to P.V.), and grants from the American Cancer Society and National Institutes of Health (to K.R.J). P.V. and C.L. are Research Associates, and L.P. is a Research Fellow, of the FNRS. A.D. and V.D. were supported by the Fonds pour la Recherche en Industrie et Agriculture (FRIA).
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Supplementary information
Supplementary Methods
Additional details of the generation of TGA7A5 BAC transgenic mice and immunohistochemistry techniques used in this study. (DOC 26 kb)
Supplementary Figure S1
Analysis of neural specification in TG/Emx1-Cre mutants. (PDF 388 kb)
Supplementary Figure S2
Analysis of neural specification in EphA7 -/- mutants. (PDF 398 kb)
Supplementary Figure S3
Patterns of expression of ephrin-A2, ephrin-A3, ephrin-A5 and EphA7 in the early mouse forebrain. (PDF 241 kb)
Supplementary Legends
Legends to accompany the above Supplementary Figures. (DOC 25 kb)
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Depaepe, V., Suarez-Gonzalez, N., Dufour, A. et al. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435, 1244–1250 (2005). https://doi.org/10.1038/nature03651
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DOI: https://doi.org/10.1038/nature03651
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