Reelin is a ligand for lipoprotein receptors

A signaling pathway involving the extracellular protein Reelin and the intr acellular adaptor protein Disabled-1 (Dab1) controls cell positioning durin g mammalian brain development. Here, we demonstrate that Reelin binds direc tly to lipoprotein receptors, preferably the very low-density lipoprotein r eceptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Binding requires calcium, and it is inhibited in the presence of apoE. Furthermore, the CR-5 0 monoclonal antibody, which inhibits Reelin function, blocks the associati on of Reelin with VLDLR. After binding to VLDLR on the cell surface, Reelin is internalized into vesicles. In dissociated neurons, apoE reduces the le vel of Reelin-induced tyrosine phosphorylation of Dab1. These data suggest that Reelin directs neuronal migration by binding to VLDLR and ApoER2.