Growth/differentiation factor 15 controls primary cilia morphology in the murine ventricular-subventricular zone thereby affecting progenitor proliferation.

Growth/differentiation factor 15 (GDF15) and its receptor GDNF Family Receptor Alpha-Like (GFRAL) are expressed from embryonic development onwards in the germinal epithelium of the ganglionic eminence (GE), regulating proliferation and number of apical progenitors. However, the mechanisms underlying this regulation are not yet clear. We here show that GDF15 exerts this regulation by affecting ciliary signalling. Not only was GFRAL localized to primary cilia but, constitutive GDF15 ablation also led to shorter and thicker primary cilia. Lack of GDF15 affected the expression of histone deacetylase 6 (HDAC6) and ciliary adenylate cyclase 3 (ADCY3), thereby modifying acetylation of microtubules and endogenous Sonic Hedgehog (SHH) activation in neural progenitors. Application of exogenous GDF15 or pharmacological antagonism of HDAC6 or ADCY3 all increased cilia length and rescued proliferation and SHH signalling in mutant but not WT progenitors. Notably, HDAC6 expression and cilia length were changed only in the GE, were ciliary GFRAL localization was observed. In contrast, GFRAL was absent from primary cilia of hippocampal progenitors where GDF15 affected ADCY3 and SHH signalling, but not HDAC6 expression or cilia morphology. We conclude that ciliary GDF15 signalling regulates HDAC6 thereby affecting primary cilia elongation and proliferation in apical progenitors.