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Cellular prion protein (PrP) is prominently expressed in brain, in differentiated neurons but also in neural stem/precursor cells (NPCs). The misfolding of PrP is a central event in prion diseases, yet the physiological function of PrP is insufficiently understood. Although PrP has been reported to associate with the neural cell adhesion molecule (NCAM), the consequences of concerted PrP‐NCAM action in NPC physiology are unknown. Here, we generated NPCs from the subventricular zone (SVZ) of postnatal day 5 wild‐type and PrP null (−/−) mice and observed that PrP is essential for proper NPC proliferation and neuronal differentiation. Moreover, we found that PrP is required for the NPC response to NCAM‐induced neuronal differentiation. In the absence of PrP, NCAM not only fails to promote neuronal differentiation but also induces an accumulation of doublecortin‐positive neuronal progenitors at the proliferation stage. In agreement, we noted an increase in cycling neuronal progenitors in the SVZ of  PrP−/−  mice compared with  PrP+/+  mice, as evidenced by double labeling for the proliferation marker Ki67 and doublecortin as well as by 5‐bromo‐2′‐deoxyuridine incorporation experiments. Additionally, fewer newly born neurons were detected in the rostral migratory stream of  PrP−/−  mice. Analysis of the migration of SVZ cells in microexplant cultures from wild‐type and  PrP−/−  mice revealed no differences between genotypes or a role for NCAM in this process. Our data demonstrate that PrP plays a critical role in neuronal differentiation of NPCs and suggest that this function is, at least in part, NCAM‐dependent. S tem  C ells   2014;32:1674–1687

stem cells

Functional Cross‐Talk Between the Cellular Prion Protein and the Neural Cell Adhesion Molecule is Critical for Neuronal Differentiation of Neural Stem/Precursor Cells