Prion protein (PrP^c) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis

The misfolding of the prion protein (PrP^c) is a central event in prion diseases, yet the normal function of PrP^c remains unknown. PrP^c has putative roles in many cellular processes including signaling, survival, adhesion, and differentiation. Given the abundance of PrP^c in the developing and mature mammalian CNS, we investigated the role of PrP^c 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 PrP^c 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 PrP^c 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 PrP^c levels positively influence neuronal differentiation in a dose-dependent manner. PrP^c also increases cellular proliferation in vivo; in the SVZ, PrP^c overexpresser (OE) mice have more proliferating cells compared with wild-type (WT) or knockout (KO) mice; in the DG, PrP^c OE and WT mice have more proliferating cells compared with KO mice. Our results demonstrate that PrP^c plays an important role in neurogenesis and differentiation. Because the final number of neurons produced in the DG is unchanged by PrP^c expression, other factors must control the ultimate fate of new neurons.