O9. Cross-talk between growth and differentiation pathways in cell fate determination in the developing brain

Abstract

Proliferation of neural stem/progenitor cells (NSCs/NPCs) is closely linked to the inhibition of neuronal and glial differentiation. However, the molecular link between induction of cell cycle progression and inhibition of cell differentiation in NSCs/NPCs is poorly understood. Fibroblast growth factor 2 (FGF2) promotes proliferation of NSCs/NPCs while it inhibits their differentiation, which suggests that a molecular link between growth and differentiation pathways is functioning downstream of FGF2 signaling. We hypothesized that a component or components in the proliferative signaling pathway should also be involved in inhibition of NSCs/NPCs differentiation. We have found that the FGF2 signaling and the Wnt canonical pathway cooperate together, via inactivation of glycogen synthase kinase 3beta (GSK3beta) and subsequent induction of cyclin D1 expression, to promote proliferation of NSCs/NPCs. Interestingly, the GSK3beta inactivation-mediated beta-catenin accumulation in the nucleus is involved in the inhibition of neurogenesis from NSCs/NPCs by activation of hes1 and hes5 gene expression through the cooperation with a Notch pathway. As we have previously demonstrated, astrocyte differentiation from NSCs/NPCs is synergistically induced by a combination of LIF and BMP2. In this symposium, we also present our recent data showing that beta-catenin stabilization by a GSK3 beta inhibitor decreases the number of GFAP expressing astrocytes in the culture of NSCs/NPCs with LIF and BMP2. In addition, forced expression of cyclin D1, a common downstream target of FGF2 and Wnt signals, decreases the number of GFAP expressing astrocytes. We further show that knockdown of cyclin D1 relieves the inhibitory effect of the GSK3beta inhibitor. In conclusion, our findings indicate that cross-interactions among growth and differentiation pathways are important for the cell-fate determination in the developing brain.