Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation

The large extracellular matrix protein Reelin is produced by Cajal-Retzius neurons in specific regions of the developing brain, where it controls neur onal migration and positioning. Genetic evidence suggests that interpretati on of the Reelin signal by migrating neurons involves two neuronal cell sur face proteins, the very low density lipoprotein receptor (VLDLR) and the ap oE receptor 2 (ApoER2) as well as a cytosolic adaptor protein, Disabled-1 ( Dab1). We show that Reelin binds directly and specifically to the ectodomai ns of VLDLR and ApoER2 in vitro and that blockade of VLDLR and ApoER2 corre lates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons. Furthermore, mice that lack either Ree lin or both VLDLR and ApoER2 exhibit hyperphosphorylation of the microtubul e-stabilizing protein tau. Taken together, these findings suggest that Reel in acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylatio n and microtubule function in neurons.