%0 Generic
%A Baur, Katja
%C Heidelberg
%D 2023
%F heidok:33630
%K GDF15; HDAC6; AC3; ADCY3; CXCR4; neural stem cells; apical; ventricular-subventricular zone; neurogenesis
%R 10.11588/heidok.00033630
%T Apical Neural Stem Cells and the Effect of Growth/Differentiation Factor 15 on their Primary Cilia and Proliferation
%U https://archiv.ub.uni-heidelberg.de/volltextserver/33630/
%X The ventricular-subventricular zone (V-SVZ) is one of the two main neurogenic niches in the mouse brain that maintains neurogenesis throughout adulthood. However, a closer characterisation of the different subtypes of the neural stem cells (NSCs) residing there, their contribution to neurogenesis and the specifics of their regulation is yet to be performed.   In the first part of this thesis, using a mouse model to genetically tag NSCs, I could show the presence of apical and basal NSCs in the adult V-SVZ. The two groups of NSCs differ in terms of Nestin expression and presence of primary cilia, which are predominantly observed in apical NSCs. Moreover, in a collaborative effort, I determined that although they also are capable of quiescence, cycling basal NSCs divide more rapidly than the apical counterpart and contribute the most to olfactory bulb neurogenesis in the adult mouse.  In the second part of this thesis, I investigated the effect of growth/differentiation factor 15 (GDF15) on NSCs in the V-SVZ. Here, I found for the first time that its only recently discovered receptor GDNF-family receptor alpha-like (GFRAL) is expressed in NSCs in the E18 lateral ganglionic eminence (GE) and adult V-SVZ, as well as in primary cilia. Using immunofluorescence on homozygous Gdf15 knock-out / LacZ knock-in (Gdf15-/-) mice, I found that ablation of GDF15 increased proliferation and cell cycle speed especially at the apical side of the niche, and that apical cells carried shorter primary cilia, a phenotype that could be rescued by application of exogenous GDF15 protein for 24 h.  To determine the mechanisms behind these changes, I first analysed epidermal growth factor (EGF) receptor (EGFR) signalling. In the mutant germinal niche, surface EGFR protein levels were lower and EGFR signalling dynamics were altered. Although exposure to GDF15 rescued EGFR surface expression, manipulation of EGFR signalling did not rescue the defect in proliferation. Instead, I found that ciliary length regulators adenylate cyclase 3 and histone deacetylase 6 were overexpressed in the mutant mice, and that their inhibition using pharmacological blockers led to a rescue of both ciliary morphology and proliferation similar to GDF15 application. Lastly, I found that sonic hedgehog signalling, a vital ciliary signalling pathway during development, was impaired but still responsive in Gdf15-/- mice, suggesting an impact of the altered ciliary morphology on organelle signalling.  All in all, in this thesis I show that apical NSCs represent a smaller subgroup of NSCs in the V-SVZ and I describe for the first time the effect of GDF15 on the development of the apical region of the V-SVZ. This effect encompasses cilia morphology and proliferation of apical progenitors affecting the generation of apical NSCs and ependymal cells in the V-SVZ.