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
Open accessAbstract
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.
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Replacing three residues upstream of the NPVY motif is sufficient to prevent DAB1 from binding APOER2 both in vitro and in vivo.
“This is in good agreement with Beffert et al. (34) who demonstrated that replacing three residues upstream of the NPVY motif is sufficient to prevent DAB1 from binding APOER2 both in vitro and in vivo.”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [34]
In “Generation and characterization of Apoer2-Dab1 binding site mutant mice” (page unavailable), the paper identifies the three substitutions and reports that mutant Apoer2 did not bind Dab1 in an in vitro pull-down assay. The Discussion (page unavailable) says examination of the mutant mice *implies* that the functional interaction was disrupted; it does not demonstrate that Dab1 binding was prevented in vivo. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApoER2 contains a multifunctional NPxY motif responsible for its signaling, endocytosis, and interaction with several adaptor proteins.
“Similar to other members of the LDL-R family, ApoER2 contains a multifunctional NPxY motif, which is responsible for its signaling [4], [11], endocytosis [24] and also the role of facilitating the interaction with several adaptor proteins [54], [55].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [11]
The Discussion identifies the ApoER2 NPXY motif as necessary for Dab1 binding and Reelin signaling, and the endocytosis section reports internalization by receptors bearing ApoER2 intracellular domains. But the Discussion places binding of the other named adaptor proteins, JIP1/2 and PSD95, at exon 19 rather than the NPXY motif; it only suggests that other proteins may also bind that motif. The paper also says endocytosis is unlikely to be a major biological function of ApoER2. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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“…ICD in exon 19, such as mitogen-activated protein kinase 8-interacting protein 1/2 (JIP1/2) and/or PSD95 (postsynaptic density 95) (Gotthardt et al., 2000; Stockinger et al., 2000), are necessary for transmitting the Reelin signal required for enhanced LTP and modulating adult memory and behavior.”
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- Authors
- Beffert, U., Durudas, A., Weeber, E. J., Stolt, P. C., Giehl, K. M., Sweatt, J. D., Hammer, R. E., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University (US)
- The University of Texas at Dallas (US)
- Baylor College of Medicine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-02-15
- Volume
- 26
- Issue
- 7
- Pages
- 2041-2052
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674917
- OpenAlex
- W2003017196
- Cited by
- 121
- References
- 3
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 6 · 2013: 7 · 2012: 6
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- Alexander von Humboldt-Stiftung
- National Institutes of Health (HL20948, HL63762)
- National Heart, Lung, and Blood Institute (HL-20948, HL63762, R37HL063762, P01HL020948)
- National Institute of Mental Health (MH 57014, R01MH057014)
- National Institute of Neurological Disorders and Stroke (NS-13546, NS43408, R01NS013546, R01NS043408)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Reelin signaling, ApoER2, Disabled-1, neuronal positioning, brain development, synaptic plasticity, long-term potentiation, hippocampus, Src family kinases, Akt signaling, mouse mutants
- MeSH terms
- Reelin Protein, Animals, Cricetinae, Humans, Nerve Tissue Proteins, Serine Endopeptidases, Signal Transduction, Cell Adhesion Molecules, Neuronal, Mutagenesis, Site-Directed, Extracellular Matrix Proteins, CHO Cells, Receptors, Lipoprotein, LDL-Receptor Related Proteins, Adaptor Proteins, Signal Transducing, Mice
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