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

GDF15 controls primary cilia morphology and function thereby affecting progenitor proliferation

“…In a previous publication, we demonstrated that ablation of GDF15 leads to an increased proliferation of embryonic apical and subapical progenitors by increasing the number of cycling cells and by promoting cell cycle progression ( Baur et al, 2024 ). Since the length of primary cilia regulates cell cycle speed ( Malicki & Johnson, 2017 ), it is possible that the changes in proliferation in mutant progenitors are associated with the defect in cilia morphology.…”

“…In a previous study, we found that both GDF15 and its receptor GFRAL are expressed at the apical side of the adult V-SVZ and in the corresponding germinal niche of the GE at embryonic day 18 (E18) ( Baur et al, 2024 ). Because apical cells characteristically extend primary cilia, we investigated if GFRAL is also present in this organelle.…”

“…Upon exposure to its ligand, GFRAL dimerizes and forms a complex with the co-receptor RET, which activates several signalling cascades, including the MAPK-ERK pathway ( Mullican et al, 2017 ) and we have recently shown that GDF15 exposure promotes ERK phosphorylation also in the embryonic GE ( Baur et al, 2024 ). Therefore, to further support the hypothesis that the effect of GDF15 on cilia depends on GFRAL activation, we next examined whether the effect of GDF15 on cilia requires ERK activation using the MEK1/2-inhibitor U0126 to inhibit phosphorylation of ERK.…”

“…Endogenous SHH activation, EGFR surface expression, and cell cycle progression are also affected in the apical GE of Gdf15 −/− E18 embryos ( Baur et al, 2024 ). To investigate the mechanisms underlying these effects of GDF15, we next analysed whether the expression of ADCY3 and HDAC6 are altered in mutant progenitors.…”

“…However, unlike the diffused expression observed in the HP, in the V-SVZ and in its largest embryonic counterpart, i.e., the germinal epithelium of the developing ganglionic eminence (GE), GDF15 and its receptor are particularly expressed on the apical side contacting the lateral ventricle ( Schober et al, 2001 ). Furthermore, unlike in the HP, in the V-SVZ GDF15 prevents proliferation of apical progenitors from late development onwards thereby decreasing the number of ependymal cells and apical NSCs in the adult V-SVZ ( Baur et al, 2024 ). Apical precursors contacting the lateral ventricle extend a primary cilium, which is important for sensing and transducing environmental signals, such as sonic hedgehog (SHH), and for cell cycle progression ( Plotnikova et al, 2009 ; Khatri et al, 2014 ).…”