Growth/differentiation factor 15 controls number of ependymal and neural stem cells in the ventricular/subventricular zone

Late in neural development, the expression of growth/differentiation factor (GDF) 15 increases in the germinal epithelium of the murine ganglionic eminence (GE). However, the function of GDF15 in this region is unknown. We here show that ablation of GDF15 leads to an increase in proliferation of apically and subapically dividing progenitors in the GE. This is associated with faster cell cycle progression in both progenitor groups, and an increase in the total number of cycling progenitors. Enhanced proliferation of apically dividing progenitors leads to a permanent significant increase in the number of ependymal and apical neural stem cells (NSCs). Our data also indicate that the extra proliferation of subapically dividing progenitors causes a transient increase in the number of neuronal progenitors, which is compensated by increased apoptosis. Independent of the genotype, activity of endogenous epidermal growth factor (EGFR) signalling is essential for the proliferation of apically and subapically dividing progenitors. However, lack of GDF15 leads to a reduced cell surface expression of EGFR and altered dynamics of MAPK activation in response to EGF stimulation. Application of exogenous GDF15 rescued the effect of the genotype on the expression of EGFR and decreased proliferation in the mutant GE. Taken together, our results indicate that GDF15 modulates proliferation and growth factor responsiveness of apical progenitors in the developing GE, thereby regulating the number of total ependymal and NSCs.