Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins

The physiological functions of the cellular prion protein, PrPC, as a cell surface pleiotropic receptor are under debate. We report that PrPC interacts with vitronectin but not with fibronectin or collagen. The binding sites mediating this PrPC-vitronectin interaction were mapped to residues 105-119 of PrPC and the residues 307-320 of vitronectin. The two proteins were co-localized in embryonic dorsal root ganglia from wild-type mice. Vitronectin addition to cultured dorsal root ganglia induced axonal growth, which could be mimicked by vitronectin peptide 307-320 and abrogated by anti-PrPC antibodies. Full-length vitronectin, but not the vitronectin peptide 307-320, induced axonal growth of dorsal root neurons from two strains of PrPC-null mice. Functional assays demonstrated that relative to wild-type cells, PrPCnull dorsal root neurons were more responsive to the Arg- Gly-Asp peptide (an integrin-binding site), and exhibited greater ALPHA-v-BETA-3 activity. Our findings indicate that PrPC plays an important role in axonal growth, and this function may be rescued in PrPC-knockout animals by integrin compensatory mechanisms. (AU)