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The Journal of Neuroscience, February 15, 2006, 26(7):2041-2052; doi:10.1523/JNEUROSCI.4566-05.2006

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Development/Plasticity/Repair
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,¹ Andre Durudas,¹ Edwin J. Weeber,⁴ Peggy C. Stolt,⁵ Klaus M. Giehl,² J. David Sweatt,⁶ Robert E. Hammer,³ and Joachim Herz¹

¹Departments of Molecular Genetics, ²Cell Biology, and ³Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ⁴Department of Molecular Physiology and Biophysics and Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, ⁵Max Planck Institute for Biophysics, D-60438 Frankfurt, Germany, and ⁶Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Joachim Herz, Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046. Email: Joachim.Herz{at}UTSouthwestern.edu

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.

Key words: signaling; neuronal migration; memory; long-term potentiation; development; phosphorylation

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Received Oct. 25, 2005; revised Jan. 4, 2005; accepted Jan. 5, 2006.

Correspondence should be addressed to Joachim Herz, Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046. Email: Joachim.Herz{at}UTSouthwestern.edu

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