Abstract
Although conversion of the cellular form of the prion protein (PrPC) into a misfolded isoform is the underlying cause of prion diseases, understanding PrPC physiological functions has remained challenging. PrPC depletion or overexpression alters the proliferation and differentiation properties of various types of stem and progenitor cells in vitro by unknown mechanisms. Such involvement remains uncertain in vivo in the absence of any drastic phenotype of mice lacking PrPC. Here, we report PrPC enrichment at the base of the primary cilium in stem and progenitor cells from the central nervous system and cardiovascular system of developing mouse embryos. PrPC depletion in a neuroepithelial cell line dramatically altered key cilium-dependent processes, such as Sonic hedgehog signalling and α-tubulin post-translational modifications. These processes were also affected over a limited time window in PrPC–ablated embryos. Thus, our study reveals PrPC as a potential actor in the developmental regulation of microtubule dynamics and ciliary functions.
Highlights
Self-renewal of haematopoietic[6] and embryonic[7,8] stem cells and to the proliferation and/or differentiation of embryonic stem cells[9] and neural progenitors[10]
To characterize how the PrPC expression pattern is specified relative to stem/progenitor cell fate in vivo, we examined the spatiotemporal distribution of PrPC in early developing wild-type mouse embryos
Tubacin affects Cyclin D1 expression to PrPC depletion, this treatment does not recapitulate the entire set of alterations of the Sonic hedgehog (Shh) signalling pathway observed in PrPnull-1C11 cells. These results suggest that PrPC depletion, rather than impaired cilia resorption, is primarily driving the changes in tubulin post-translational modifications (PTMs) and Shh signalling observed in PrPnull-1C11 cells
Summary
Self-renewal of haematopoietic[6] and embryonic[7,8] stem cells and to the proliferation and/or differentiation of embryonic stem cells[9] and neural progenitors[10]. To characterize how the PrPC expression pattern is specified relative to stem/progenitor cell fate in vivo, we examined the spatiotemporal distribution of PrPC in early developing wild-type mouse embryos. In the mouse developing neural tube and even more markedly in a neuroepithelial cell line displaying neuroectodermal progenitor hallmarks, the depletion of PrPC altered key cilium-dependent processes and pathways, including α -tubulin post-translational modifications (PTMs) and the Sonic hedgehog signalling pathway. These data reveal a new link between PrPC and microtubule dynamics as well as primary cilium functions during development
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