Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis

Andrew D. Steele, Jason G. Emsley, P. Hande Özdinler, Susan Lindquist*, Jeffrey D. Macklis

*Corresponding author for this work

Research output: Contribution to journalArticle

202 Scopus citations

Abstract

The misfolding of the prion protein (PrPc) is a central event in prion diseases, yet the normal function of PrPc remains unknown. PrPc has putative roles in many cellular processes including signaling, survival, adhesion, and differentiation. Given the abundance of PrPc in the developing and mature mammalian CNS, we investigated the role of PrPc in neural development and in adult neurogenesis, which occurs constitutively in the dentate gyrus (DG) of the hippocampus and in the olfactory bulb from precursors in the subventricular zone (SVZ)/rostral migratory stream. In vivo, we find that PrPc is expressed immediately adjacent to the proliferative region of the SVZ but not in mitotic cells. In vivo and in vitro studies further find that PrPc is expressed in multipotent neural precursors and mature neurons but is not detectable in glia. Loss-and gain-of-function experiments demonstrate that PrPc levels correlate with differentiation of multipotent neural precursors into mature neurons in vitro and that PrPc levels positively influence neuronal differentiation in a dose-dependent manner. PrPc also increases cellular proliferation in vivo; in the SVZ, PrPc overexpresser (OE) mice have more proliferating cells compared with wild-type (WT) or knockout (KO) mice; in the DG, PrPc OE and WT mice have more proliferating cells compared with KO mice. Our results demonstrate that PrPc plays an important role in neurogenesis and differentiation. Because the final number of neurons produced in the DG is unchanged by PrPc expression, other factors must control the ultimate fate of new neurons.

Original languageEnglish (US)
Pages (from-to)3416-3421
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number9
DOIs
StatePublished - Feb 28 2006

Keywords

  • Dentate gyrus
  • Neural development
  • Neural precursor
  • Subventricular zone

ASJC Scopus subject areas

  • General

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