title: 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, 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 PrPCdepletion, we establish that PrPCdeficiency severely affects the Notch pathway, which plays a major role in neural stem cell maintenance. We document that the absence of PrPCin 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 PrPCresults in altered expression of Nestin and Olig2 as well as N-cadherin distribution. We further provide evidence that PrPCcontrols 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 PrPCtakes part to the self-renewal of neural stem and progenitor cells. Stem Cells 2017;35:754-765.
authors.affiliation: INSERM UMR 1124, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR 1124, Paris, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Martin-Lannerée
authors.affiliation: VIM, UR 892, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Halliez
authors.affiliation: INSERM UMR 1124, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR 1124, Paris, France.
authors.forename: Théo Z
authors.initials: TZ
authors.lastname: Hirsch
authors.affiliation: INSERM UMR 1124, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR 1124, Paris, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Hernandez-Rapp
authors.affiliation: Department of Pharma Research, INRA UMR 1313, Génétique animale et biologie intégrative, Jouy-en-Josas, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Passet
authors.affiliation: INSERM UMR 1124, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR 1124, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Tomkiewicz
authors.affiliation: Centro de Investigación en Sanidad Animal-INIA, U 942 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Villa-Diaz
authors.affiliation: Centro de Investigación en Sanidad Animal-INIA, U 942 Madrid, Spain.
authors.forename: Juan-Maria
authors.initials: JM
authors.lastname: Torres
authors.affiliation: AP-HP Service de Biochimie, Fondation FondaMental, INSERM U942 Hôpital Lariboisière, Paris, France.|Pharma Research Department, F. Hoffmann-La-Roche Ltd, Basel, Switzerland.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: VIM, UR 892, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Béringue
authors.affiliation: Department of Pharma Research, INRA UMR 1313, Génétique animale et biologie intégrative, Jouy-en-Josas, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vilotte
authors.affiliation: INSERM UMR 1124, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR 1124, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mouillet-Richard
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D002460:Cell Line; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism*; D000072002:Prion Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D015820:Cadherins; D000072002:Prion Proteins; D051880:Receptors, Notch; D066246:ErbB Receptors
keywords: Cadherins; Epidermal growth factor receptor; Neural stem cells; Notch; Prion protein