BMP2 and FGF2 cooperate to induce neural-crest-like fates from fetal and adult CNS stem cells

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Abstract
CNS stem cells are best characterized by their ability to self-renew and to generate multiple differentiated derivatives, but the effect of mitogenic signals, such as fibroblast growth factor 2 (FGF2), on the positional identity of these cells is not well understood. Here, we report that bone morphogenetic protein 2 (BMP2) induces telencephalic CNS stem cells to fates characteristic of neural crest and choroid plexus mesenchyme, a cell type of undetermined lineage in rodents. This induction occurs both in dissociated cell culture and cortical explants of embryonic day 14.5 (E14.5) embryos, but only when cells have been exposed to FGF2. Neither EGF nor IGF1 can substitute for FGF2. An early step in this response is activation of β-catenin, a mediator of Wnt activity. The CNS stem cells first undergo an epithelial-to-mesenchymal transition and subsequently differentiate to smooth-muscle and non-CNS glia cells. Similar responses are seen with stem cells from E14.5 cortex, E18.5 cortex and adult subventricular zone, but with a progressive shift toward gliogenesis that is characteristic of normal development. These data indicate that FGF2 confers competence for dorsalization independently of its mitogenic action. This rapid and efficient induction of dorsal fates may allow identification of positional identity effectors that are co-regulated by FGF2 and BMP2.