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

Abstract

AbstractLate in neural development, the expression of growth/differentiation factor (GDF) 15 increases in the germinal epithelium of the murine ganglionic eminence (GE) especially in progenitors with characteristics of neural stem cells (NSCs) and expressing high levels of epidermal growth factor receptor (EGFRh). However, the function of GDF15 in this region is unknown. We here show that apical EGFR immunopositive progenitors in the embryonic GE also express the receptor for GDF15 and that ablation of the latter affects the number and cell division dynamics of apically and subapically dividing progenitors. Apical proliferation is increased also in the adult mutant ventricular-subventricular zone (V-SVZ), which displays more ependymal and apical NSCs than the WT counterpart. In addition, we observed a transient increase in the number of neuronal progenitors, which was compensated by increased apoptosis. From a mechanistic point of view, we show that active EGFR is essential to maintain proliferation in the developing GE and that GDF15 affects EGFR trafficking and signal transduction. Consistent with a direct involvement of GDF15, exposure of the GE to the growth factor normalized proliferation and EGFR expression and it decreased the number of apical progenitors. A similar decrease in the number of apical progenitors was also observed upon exposure to exogenous EGF. However, this effect was not associated with reduced proliferation, illustrating the complexity of the effect of GDF15. Taken together, our results indicate that GDF15 modulates proliferation and EGF responsiveness of apical progenitors in the developing GE, thereby regulating the number of total ependymal and NSCs.