Functional dissection of Reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2

Distinct roles in development and synaptic plasticity

Uwe Beffert, Andre Durudas, Edwin J. Weeber, Peggy C. Stolt, Klaus M. Giehl, J. David Sweatt, Robert E Hammer, Joachim Herz

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

The Reelin signaling pathway controls neuronal positioning in human and mouse brain during development as well as modulation of long-term potentiation (LTP) and behavior in the adult. Reelin signals by binding to two transmembrane receptors, apolipoprotein E receptor 2 (Apoer2) and very-low-density lipoprotein receptor. After Reelin binds to the receptors, Disabled-1 (Dab1), an intracellular adaptor protein that binds to the cytoplasmic tails of the receptors, becomes phosphorylated on tyrosine residues, initiating a signaling cascade that includes activation of Src-family kinases and Akt. Here, we have created a line of mutant mice (Apoer2 EIG) in which the Apoer2 NFDNPVY motif has been altered to EIGNPVY to disrupt the Apoer2-Dab1 interaction to further study Reelin signaling in development and adult brain. Using primary neuronal cultures stimulated with recombinant Reelin, we find that normal Reelin signaling requires the wild-type NFDNPVY sequence and likely the interaction of Apoer2 with Dab1. Furthermore, examination of hippocampal, cortical, and cerebellar layering reveals that the NFDNPVY sequence of Apoer2 is indispensable for normal neuronal positioning during development of the brain. Adult Apoer2 EIG mice display severe abnormalities in LTP and behavior that are distinct from those observed for mice lacking Apoer2. In Apoer2 EIG slices, LTP degraded to baseline within 30 min, and this was prevented in the presence of Reelin. Together, these findings emphasize the complexity of Reelin signaling in the adult brain, which likely requires multiple adaptor protein interactions with the intracellular domain of Apoer2.

Original languageEnglish (US)
Pages (from-to)2041-2052
Number of pages12
JournalJournal of Neuroscience
Volume26
Issue number7
DOIs
StatePublished - Feb 15 2006

Fingerprint

Neuronal Plasticity
Dissection
Long-Term Potentiation
Brain
low density lipoprotein receptor-related protein 8
src-Family Kinases
Cytoplasmic and Nuclear Receptors
Tyrosine
Tail
Proteins

Keywords

  • Development
  • Long-term potentiation
  • Memory
  • Neuronal migration
  • Phosphorylation
  • Signaling

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Functional dissection of Reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2 : Distinct roles in development and synaptic plasticity. / Beffert, Uwe; Durudas, Andre; Weeber, Edwin J.; Stolt, Peggy C.; Giehl, Klaus M.; Sweatt, J. David; Hammer, Robert E; Herz, Joachim.

In: Journal of Neuroscience, Vol. 26, No. 7, 15.02.2006, p. 2041-2052.

Research output: Contribution to journalArticle

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