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

Thomas Hiesberger, Marion Trommsdorff, Brian W. Howell, Andre Goffinet, Marc C. Mumby, Jonathan A. Cooper, Joachim Herz

Research output: Contribution to journalArticle

713 Scopus citations

Abstract

The large extracellular matrix protein Reelin is produced by Cajal- Retzius neurons in specific regions of the developing brain, where it controls neuronal migration and positioning. Genetic evidence suggests that interpretation of the Reelin signal by migrating neurons involves two neuronal cell surface proteins, the very low density lipoprotein receptor (VLDLR) and the apoE receptor 2 (ApoER2) as well as a cytosolic adaptor protein, Disabled-1 (Dab1). We show that Reelin binds directly and specifically to the ectodomains of VLDLR and ApoER2 in vitro and that blockade of VLDLR and ApoER2 correlates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons. Furthermore, mice that lack either Reelin or both VLDLR and ApoER2 exhibit hyperphosphorylation of the microtubule-stabilizing protein tau. Taken together, these findings suggest that Reelin acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylation and microtubule function in neurons.

Original languageEnglish (US)
Pages (from-to)481-489
Number of pages9
JournalNeuron
Volume24
Issue number2
DOIs
StatePublished - Oct 1999

ASJC Scopus subject areas

  • Neuroscience(all)

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