GDF15 controls primary cilia morphology and function thereby affecting progenitor proliferation.

We recently reported that growth/differentiation factor 15 (GDF15) and its receptor GDNF family receptor alpha-like (GFRAL) are expressed in the periventricular germinal epithelium thereby regulating apical progenitor proliferation. However, the mechanisms are unknown. We now found GFRAL in primary cilia and altered cilia morphology upon GDF15 ablation. Mutant progenitors also displayed increased histone deacetylase 6 (Hdac6) and ciliary adenylate cyclase 3 (Adcy3) transcript levels. Consistently, microtubule acetylation, endogenous sonic hedgehog (SHH) activation and ciliary ADCY3 were all affected in this group. Application of exogenous GDF15 or pharmacological antagonists of either HDAC6 or ADCY3 similarly normalized ciliary morphology, proliferation and SHH signalling. Notably, Gdf15 ablation affected Hdac6 expression and cilia length only in the mutant periventricular niche, in concomitance with ciliary localization of GFRAL. In contrast, in the hippocampus, where GFRAL was not expressed in the cilium, progenitors displayed altered Adcy3 expression and SHH signalling, but Hdac6 expression, cilia morphology and ciliary ADCY3 levels remained unchanged. Thus, ciliary signalling underlies the effect of GDF15 on primary cilia elongation and proliferation in apical progenitors.

Growth/differentiation factor 15 controls ependymal and stem cell number in the V-SVZ.

The expression of growth/differentiation factor (GDF) 15 increases in the ganglionic eminence (GE) late in neural development, especially in neural stem cells (NSCs). However, GDF15 function in this region remains unknown. We report that GDF15 receptor is expressed apically in the GE and that GDF15 ablation promotes proliferation and cell division in the embryonic GE and in the adult ventricular-subventricular zone (V-SVZ). This causes a transient generation of additional neuronal progenitors, compensated by cell death, and a lasting increase in the number of ependymal cells and apical NSCs. Finally, both GDF15 receptor and the epidermal growth factor receptor (EGFR) were expressed in progenitors and mutation of GDF15 affected EGFR signaling. However, only exposure to exogenous GDF15, but not to EGF, normalized proliferation and the number of apical progenitors. Thus, GDF15 regulates proliferation of apical progenitors in the GE, thereby affecting the number of ependymal cells and NSCs.