The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

The prion protein is infamous for its involvement in a group of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies. In the longstanding quest to decipher the physiological function of its cellular isoform, PrPC, the discovery of its participation to the self‐renewal of hematopoietic and neural stem cells has cast a new spotlight on its potential role in stem cell biology. However, still little is known on the cellular and molecular mechanisms at play. Here, by combining in vitro and in vivo murine models of PrPC depletion, we establish that PrPC deficiency severely affects the Notch pathway, which plays a major role in neural stem cell maintenance. We document that the absence of PrPC in a neuroepithelial cell line or in primary neurospheres is associated with drastically reduced expression of Notch ligands and receptors, resulting in decreased levels of Notch target genes. Similar alterations of the Notch pathway are recovered in the neuroepithelium of Prnp−/− embryos during a developmental window encompassing neural tube closure. In addition, in line with Notch defects, our data show that the absence of PrPC results in altered expression of Nestin and Olig2 as well as N‐cadherin distribution. We further provide evidence that PrPC controls the expression of the epidermal growth factor receptor (EGFR) downstream from Notch. Finally, we unveil a negative feedback action of EGFR on both Notch and PrPC. As a whole, our study delineates a molecular scenario through which PrPC takes part to the self‐renewal of neural stem and progenitor cells. Stem Cells 2017;35:754–765 Model for PrPC action on Notch and stemness in neural progenitors: PrPC positively regulates the expression of Notch ligands and that of the Notch receptors and its ablation compromises Notch signaling; proper Notch signaling supports N‐cadherin‐mediated cell‐cell contacts as well as the expression of NSC markers and exerts a positive feedback action on PrPC; downstream from PrPC, Notch signaling additionally upregulates the expression of EGFR, which, when activated, negatively regulates both PrPC and Notch. Thus, PrPC, the Notch pathway and EGFR belong to a gene regulatory network, whose imbalance may shift toward “more stemness” (higher Notch activity induces higher PrPC expression and vice versa) or “less stemness” (EGFR activation dampens Notch signaling and PrPC expression).