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

Abstract

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, PrP , 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 PrP depletion, we establish that PrP deficiency severely affects the Notch pathway, which plays a major role in neural stem cell maintenance. We document that the absence of PrP 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 PrP results in altered expression of Nestin and Olig2 as well as N-cadherin distribution. We further provide evidence that PrP 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 PrP . As a whole, our study delineates a molecular scenario through which PrP takes part to the self-renewal of neural stem and progenitor cells. Stem Cells 2017;35:754-765.

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

“…This observation is in line with previous studies showing that PrP C during development and adulthood controls OPC proliferation and oligodendroglial differentiation; PrP C knock-out mice show increased OPC proliferation, decreased oligodendroglial differentiation and increased numbers of OPCs in adulthood without changes in myelination (Bribián et al, 2012). The effect of PrP upon stem/progenitor cell signaling is through modulation of Notch (Martin-Lannere et al, 2017).…”

Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression

“…The normal cellular prion protein (PrP C ) is a highly conserved and ubiquitous glycoprotein, which is mostly tethered to the cell surface by the glycosylphosphatidylinositol anchor . Although the abnormal form of the prion protein (PrP) is involved in the pathogenesis of prion diseases and neurodegenerative disorders, emerging data suggest that PrP C is a key molecule with fundamental roles in stem cell proliferation and self‐renewal, as well as protecting against neurodegeneration . In addition, several studies have indicated that PrP C is involved in stem and/or progenitor cell differentiation, neurogenesis, and angiogenesis .…”

“…Although the abnormal form of the prion protein (PrP) is involved in the pathogenesis of prion diseases and neurodegenerative disorders, emerging data suggest that PrP C is a key molecule with fundamental roles in stem cell proliferation and self‐renewal, as well as protecting against neurodegeneration . In addition, several studies have indicated that PrP C is involved in stem and/or progenitor cell differentiation, neurogenesis, and angiogenesis . Therefore, it is of great interest to understand the pivotal role of PrP C and the mechanism that underlies protection of transplanted MSCs in pathophysiological conditions.…”

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

“…Additionally, HSPA1L binds to OCT4 in cancer stem cells, resulting in maintenance of stemness (Lee et al, ). PrP C , the normal cellular prion protein, is a pivotal molecule with fundamental roles in self‐renewal, proliferation, and angiogenesis of stem/progenitor cells (Lee, Han, & Lee, ; Martin‐Lanneree et al, ; Martin‐Lanneree et al, ). Treatment with melatonin increases the function of MSCs through upregulation of PrP C , resulting in improvement of neovascularization in ischemic tissues (Lee, Han, & Lee, ).…”