Emx2 expression levels in NSCs modulate astrogenesis rates by regulating EgfR and Fgf9

Generation of astrocytes within the developing cerebral cortex is a tightly regulated process, initiating at low level in the mid- dle of neuronogenesis and peaking up after its completion. Astrocytic outputs depend on two primary factors: progression of multipotent precursors toward the astroglial lineage and sizing of the astrogenic proliferating pool. The aim of this study was to investigate the role of the Emx2 homeobox gene in the latter process. We addressed this issue by combined gain- and loss-of-function methods, in vivo as well as in primary cultures of cortico-cerebral precursors. We found that Emx2 overexpres- sion in cortico-cerebral stem cells shrinked the proliferating astrogenic pool, resulting in a severe reduction of the astroglial outcome. We showed that this was caused by EgfR and Fgf9 downregulation and that both phenomena originated from exaggerated Bmp signaling and Sox2 repression. Finally, we provided evidence that in vivo temporal progression of Emx2 levels in cortico-cerebral multipotent precursors contributes to confine the bulk of astrogenesis to postnatal life. Emx2 regula- tion of astrogenesis adds to a number of earlier developmental processes mastered by this gene. It points to Emx2 as a new promising tool for controlling reactive astrogliosis and optimizing cell-based designs for brain repair. © 2014 Wiley Periodicals, Inc.