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

The physiological functions of the cellular prion protein, PrP^C, as a cell surface pleiotropic receptor are under debate. We report that PrP^C interacts with vitronectin but not with fibronectin or collagen. The binding sites mediating this PrP^C-vitronectin interaction were mapped to residues 105-119 of PrP^C 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-PrP^C antibodies. Full-length vitronectin, but not the vitronectin peptide 307-320, induced axonal growth of dorsal root neurons from two strains of PrP^C-null mice. Functional assays demonstrated that relative to wild-type cells, PrP^C-null dorsal root neurons were more responsive to the Arg-Gly-Asp peptide (an integrin-binding site), and exhibited greater v3 activity. Our findings indicate that PrP^C plays an important role in axonal growth, and this function may be rescued in PrP^C-knockout animals by integrin compensatory mechanisms.