The DOI matches its Crossref record; 50 of the 52 references it cites were found in a registry or an index; none of the 1 sources its claims cite is checked for support yet.
Reelin Is a Ligand for Lipoprotein Receptors
Open accessAbstract
A signaling pathway involving the extracellular protein Reelin and the intracellular adaptor protein Disabled-1 (Dab1) controls cell positioning during mammalian brain development. Here, we demonstrate that Reelin binds directly to lipoprotein receptors, preferably the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Binding requires calcium, and it is inhibited in the presence of apoE. Furthermore, the CR-50 monoclonal antibody, which inhibits Reelin function, blocks the association of Reelin with VLDLR. After binding to VLDLR on the cell surface, Reelin is internalized into vesicles. In dissociated neurons, apoE reduces the level of Reelin-induced tyrosine phosphorylation of Dab1. These data suggest that Reelin directs neuronal migration by binding to VLDLR and ApoER2.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This study reports that Reelin acts as a ligand for the lipoprotein receptors VLDLR and ApoER2, with binding dependent on calcium and inhibited by apoE. The authors propose that Reelin binding to these receptors leads to Reelin internalization and altered Dab1 tyrosine phosphorylation, thereby influencing neuronal positioning during brain development.
Key findings
- Reelin associated with cells expressing VLDLR or ApoER2, and to a lesser extent LDLR, but not with mock-transfected cells or cells expressing APLP1. Under the assay conditions, VLDLR- or ApoER2-expressing cells bound about 26% of applied Reelin, whereas LDLR-expressing cells bound about 8%; full-length Reelin bound more efficiently than truncated forms (32% for full-length, 17% for the 250 kDa form, and 9% for the 180 kDa form).
- Binding required calcium: EGTA or EDTA abolished Reelin association with VLDLR and ApoER2, and added calcium restored it. The CR-50 anti-Reelin antibody reduced binding to VLDLR by 64% at 115 µg/ml and by 84% at 300 µg/ml, while G10 antibody or control IgG did not inhibit.
- Reelin was internalized after binding VLDLR, appearing in vesicular structures at 37°C but not at 4°C. Recombinant apoE3 inhibited Reelin binding to ApoER2 by about 50%; apoE3 and apoE4 inhibited binding to VLDLR by about 60%, whereas apoE2 inhibited by about 10%.
- In embryonic cortical neurons, Reelin alone caused a 3-fold increase in Dab1 tyrosine phosphorylation; apoE3 reduced this Reelin-induced increase by about 50% and slightly lowered basal Dab1 phosphorylation by about 10%. Half-maximum binding to VLDLR occurred at 0.7 nM Reelin, an apparent affinity comparable to that of RAP.
Methods
- 293T cells were transfected with VLDLR, ApoER2, LDLR, APLP1, or no DNA, then incubated with Reelin-containing conditioned medium from pCrl-transfected 293T cells. Bound Reelin was detected by Western blotting, with additional assays for time course, dose dependence, antibody inhibition, calcium dependence, and apoE competition.
- COS-7 cells expressing VLDLR were used for immunocytochemistry after Reelin treatment at 37°C or 4°C to assess cell-surface binding and internalization.
- Dissociated cortical neurons from embryonic day 16.5 mice were treated with Reelin with or without recombinant apoE3; Dab1 was immunoprecipitated and analyzed by Western blotting for phosphotyrosine and total Dab1.
Limitations
- The paper states that a purified Reelin preparation with known concentration and activity was unavailable, so the affinity for lipoprotein receptors could not be measured accurately; the reported value is an apparent affinity estimate.
- The authors state they cannot formally exclude participation of other cell-surface molecules in Reelin signal transduction, although their binding studies found no evidence for a required coreceptor.
- The paper notes that the kinase responsible for Reelin-induced Dab1 tyrosine phosphorylation remains unidentified, and it is unclear which tyrosine kinases are involved.
- Evident from the text: most binding and internalization experiments used transfected non-neuronal cell lines with overexpressed receptors, and the neuronal signaling data are in vitro, so the findings may not fully capture endogenous receptor behavior or in vivo function.
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Claims the paper makes
2 Own result · 1 Not checked yet · 1 Own method · 1 Own interpretation · 1 No basis given
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“After binding to VLDLR on the cell surface, Reelin is internalized into vesicles.”
§ Reelin Is a Ligand for Lipoprotein Receptors cerebellum, that lead to the formation of cell layers and > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not find any evidence for a coreceptor molecule in our binding studies since Reelin did not associate with 293T or COS cells in the absence of transfected lipoprotein receptors.”
§ Reelin Is a Ligand for Lipoprotein Receptors cerebellum, that lead to the formation of cell layers and > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We determined that Reelin was not depleted from the conditioned medium during the course of the experiments by dot blot analysis.”
§ Reelin Is a Ligand for Lipoprotein Receptors cerebellum, that lead to the formation of cell layers and > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 3
- The quote only partly states this claim. 1
- Probably not a substantial claim. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Binding approached saturation within 1 hr.”
§ Reelin Is a Ligand for Lipoprotein Receptors cerebellum, that lead to the formation of cell layers and > Abstract
plaincorrelational- Asserted: unclear — It is unclear whether the authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one. The quote only partly states this claim.
In the paper
“However, RAP is an intracellular chaperone and not a physiological extracellular ligand (Willnow et al., 1996).”
§ Reelin Is a Ligand for Lipoprotein Receptors cerebellum, that lead to the formation of cell layers and > Abstract
What the sources say
- Not checked yetcites Willnow et al., 1996 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the simplest interpretation of our data is that VLDLR and ApoER2 function as receptors for Reelin.”
§ Reelin Is a Ligand for Lipoprotein Receptors cerebellum, that lead to the formation of cell layers and > Abstract
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The binding of Reelin to transfected lipoprotein receptors in cultured cells reflects the physiological receptor interaction that directs neuronal positioning in vivo.
The paper relies on this without support.
The binding of Reelin to transfected lipoprotein receptors in cultured cells reflects the physiological receptor interaction that directs neuronal positioning in vivo.
“Although we cannot formally rule out the possibility that other cell surface molecules participate in Reelin signal transduction, the simplest interpretation of our data is that VLDLR and ApoER2 function as receptors for Reelin.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“possibly giving it a competitive advantage for binding to its receptors7.”
From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These results suggest that Reelin controls neuronal migration and positioning by stimulating tyrosine phosphorylation of Dab1 via VLDLR, ApoER2, and CNR family proteins.”
From Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody (2000) · cites this paper as [35]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The binding of RELN results in the clustering and activation of VLDLr and APOEr2, initiating a signaling pathway that leads to the activation of Dab1 (refs. 4,7–9).”
From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“apoE is known to interfere with reelin binding to ApoER2 (D’Arcangelo et al., 1999).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as D’Arcangelo et al., 1999
The cited source says what the claim attributes to it.
In the citing paper
“A body of evidence demonstrates that the VLDLR and ApoER2 interact with an extracellular ligand, Reelin, leading, as a first event, to phosphorylation of the adaptor molecule Dab1 (20, 21).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“Reelin interaction with the VLDLR and ApoER2 is critical during development because it properly directs the positioning of neurons (16, 20, 21).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“In addition to their proposed roles in metabolism, the VLDLR and ApoER2 are critical for neuronal migration during development (16, 20, 21).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“ApoER2 binds the extracellular matrix protein reelin during development [4], [6], triggering a signaling pathway that regulates neuronal migration and the formation of laminated brain structures such as the cortex, hippocampus [7] and cerebellum [4]”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [6]
In the citing paper
“Reelin binding to the lipoprotein receptor-expressing cells was reduced to 36% and 16% at 115 and 300 μg/ml CR-50 antibody, respectively (35).”
From Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody (2000) · cites this paper as [35]
In the citing paper
“CR-50 antibody inhibited Reelin binding to VLDLR-expressing 293T cells (35) and to the extracellular domain of CNR1 protein (37).”
From Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody (2000) · cites this paper as [35]
In the citing paper
“Because the Dab1 phosphorylation is essential in Reelin signaling (24, 35–37)”
From Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody (2000) · cites this paper as [35]
In the citing paper
“Recently, lipoprotein receptors (VLDLR and ApoER2) and the CNR family members were reported to bind to the full-length Reelin (35–37).”
From Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody (2000) · cites this paper as [35]
In the citing paper
“Reelin binds to several protein receptors, including very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 and α3β1 integrin [144–146].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [144]
Citations
Cites
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
A protein related to extracellular matrix proteins deleted in the mouse mutant reeler
D'Arcangelo, G., G. Miao, G., Chen, S.-C., Scares, H. D., Morgan, J. I., & Curran, T. (1995) · Nature · doi:10.1038/374719a0 · Cited by 1,748
Self-citationTrommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., & Herz, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80782-5 · Cited by 1,261
Ohshima, T., Ward, J. M., Huh, C. G., Longenecker, G., Veeranna, Pant, H. C., Brady, R. O., Martin, L. J., & Kulkarni, A. B. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.20.11173 · Cited by 897
Ogawa, M., Miyata, T., Nakajimat, K., Yagyu, K., Seike, M., Ikenaka, K., Yamamoto, H., & Mikoshibat, K. (1995) · Neuron · doi:10.1016/0896-6273(95)90329-1 · Cited by 889 · cited 5×
“Reelin binding to the VLDLR was modest atReelin amino acids 250–407 (Ogawa et al., 1995; D’Arca concentration range of 0.08 to 0.31 nM, but it increasedangelo et al., 1997).”
BackgroundInfluentialChen, W. J., Goldstein, J. L., & Brown, M. S. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)39742-x · Cited by 731
Chae, T., Kwon, Y. T., Bronson, R., Dikkes, P., Li, E., & Tsai, L.-H. (1997) · Neuron · doi:10.1016/s0896-6273(01)80044-1 · Cited by 715
Apolipoprotein E and Alzheimer disease.
Strittmatter, W. J., & Roses, A. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.4725 · Cited by 701
Neuronal position in the developing brain is regulated by mouse disabled-1
Howell, B. W., Hawkes, R., Soriano, P., & Cooper, J. A. (1997) · Nature · doi:10.1038/39607 · Cited by 692
Research works printed but not linked: 1
- Willnow, 1998, Receptor-associated protein (RAP), Biol. Chem., 379, 1025
Cited by
Sorted by citations
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,951
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836
Guidotti, A., Auta, J., Davis, J. M., Gerevini, V. D. G., Dwivedi, Y., Grayson, D. R., Impagnatiello, F., Pandey, G. N., Pesold, C., Sharma, R. P., et al. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.11.1061 · Cited by 1,222
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168
“Although biochemical evidence suggests that APOE interferes with reelin binding to APOE receptor”
BackgroundC ELL M IGRATION IN THE F OREBRAIN
Marín, Ó., & Rubenstein, J. L. R. (2003) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.26.041002.131058 · Cited by 957
Metadata
- Authors
- D'Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D. S., Sheldon, M., & Curran, T.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Curran, Tom
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 24
- Issue
- 2
- Pages
- 471-479
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2033822739
- Cited by
- 808
- References
- 52
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 23 · 2022: 24 · 2021: 24 · 2020: 19 · 2019: 13 · 2018: 20 · 2017: 32 · 2016: 25 · 2015: 20 · 2014: 32 · 2013: 33 · 2012: 33
- FWCI
- 15.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (T32CA09346, T32CA009346, P 30CA 21765, P30CA021765)
- National Institute of Neurological Disorders and Stroke (R01 NS36558, R01NS036558)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- reelin, lipoprotein receptors, VLDLR, ApoER2, Disabled-1, receptor binding, calcium-dependent binding, apolipoprotein E, neuronal migration, brain development, receptor internalization, tyrosine phosphorylation
- MeSH terms
- Reelin Protein, Animals, Calcium, Cell Line, Cells, Humans, Ligands, Nerve Tissue Proteins, Receptors, LDL, Serine Endopeptidases, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Receptors, Lipoprotein, COS Cells, Low Density Lipoprotein Receptor-Related Protein-1, Mice
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