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.
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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
0 of 1 cited sources checked · 0 supported · 0 flagged
- Findingnone given
Reelin bound to VLDLR at the cell surface is internalized into vesicles.
“After binding to VLDLR on the cell surface, Reelin is internalized into vesicles.”
Quote in the paperSubstantial claim - Findingown data
No coreceptor was evident because Reelin did not bind 293T or COS cells without transfected lipoprotein receptors.
“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.”
Quote in the paperSubstantial claim - Study design and conductown data
Reelin was not depleted from conditioned medium during the binding experiments, according to dot blot analysis.
“We determined that Reelin was not depleted from the conditioned medium during the course of the experiments by dot blot analysis.”
Quote in the paperSubstantial claim
- May combine two claims. 3
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 1
May combine two claims. The quote only partly states this claim.
Findingown dataReelin binding to VLDLR is rapid, reaching about 16% within 5 minutes and nearing saturation by 1 hour.
“Binding approached saturation within 1 hr.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRAP is an intracellular chaperone, not a physiological extracellular ligand.
“However, RAP is an intracellular chaperone and not a physiological extracellular ligand (Willnow et al., 1996).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Willnow et al., 1996 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe simplest reading of the data is that VLDLR and ApoER2 serve as Reelin receptors.
“the simplest interpretation of our data is that VLDLR and ApoER2 function as receptors for Reelin.”
Quote in the paperSubstantial claim- 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 RELN-COLBOS variant possibly gives RELN a competitive advantage for binding to its receptors.
“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]
The binding experiments (Figure 1B and Figure 4) show that Reelin binds ApoER2 and VLDLR, with high apparent affinity for VLDLR. They do not examine the RELN-COLBOS variant or whether it has a competitive binding advantage over other forms of Reelin. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe binding of RELN results in clustering and activation of VLDLr and APOEr2, initiating a signaling pathway that leads to activation of Dab1.
“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 measuredApoE is known to interfere with reelin binding to ApoER2.
“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
VLDLR and ApoER2 interact with Reelin, leading to phosphorylation of Dab1.
“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]
Reelin interaction with the VLDLR and ApoER2 is critical during development because it properly directs the positioning of neurons.
“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 VLDLR and ApoER2 are critical for neuronal migration during development.
“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]
ApoER2 binds reelin during development, triggering a signaling pathway that regulates neuronal migration and the formation of laminated brain structures such as the cortex, hippocampus and cerebellum.
“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]
Reelin controls neuronal migration and positioning by stimulating tyrosine phosphorylation of Dab1 via VLDLR, ApoER2, and CNR family proteins.
“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]
Reelin binding to lipoprotein receptor-expressing cells was reduced to 36% and 16% at 115 and 300 μg/ml CR-50 antibody, respectively.
“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]
CR-50 antibody inhibited Reelin binding to VLDLR-expressing 293T cells and to the extracellular domain of CNR1 protein.
“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]
Dab1 phosphorylation is essential in Reelin signaling.
“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]
Lipoprotein receptors (VLDLR and ApoER2) and CNR family members bind to full-length Reelin.
“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]
Reelin binds to VLDLR, apolipoprotein E receptor 2, and α3β1 integrin.
“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]
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“fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=16975">APOER2 is the receptor for REELIN , an extracellular protein that is defective in the reeler mouse, which has ataxia, a typical reeling gait and abnormal neuronal organizatio”
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Reelin Binds α3β1 Integrin and Inhibits Neuronal Migration
Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., & Anton, E. S. (2000) · Neuron · doi:10.1016/s0896-6273(00)00007-6 · Cited by 577 · see citing works
Reelin, lipoprotein receptors and synaptic plasticity
Herz, J., & Chen, Y. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn2009 · Cited by 524 · see citing works
“A few years later, neuronal lipoprotein receptors — that is, a class of cell surface proteins ( Box 1 ) that can bind APOE and transport cholesterol into the cell — were found to serve as receptors for the developmental signalling protein reelin in pivotal signal transduction events that control the migration of neuro…”
BackgroundExtracellular Matrix: Functions in the Nervous System
Barros, C. S., Franco, S. J., & Muller, U. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005108 · Cited by 506 · see citing works
“Reelin binds to the lipoprotein receptors ApoER2 and VLDLR (D’Arcangelo et al. 1999), which are expressed by migrating neurons and RGCs (Luque et al. 2003).”
BackgroundInfluentialBeffert, U., Weeber, E. J., Durudas, A., Qiu, S., Masiulis, I., Sweatt, J. D., Li, W.-P., Adelmann, G., Frotscher, M., Hammer, R. E., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.07.007 · Cited by 497 · see citing works
Lipoprotein receptors in the nervous system
Herz, J., & Bock, H. H. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.110601.135342 · Cited by 457 · see citing works
Gotthardt, M., Trommsdorff, M., Nevitt, M. F., Shelton, J., Richardson, J. A., Stockinger, W., Nimpf, J., & Herz, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000955200 · Cited by 450 · see citing works
Guiding Neuronal Cell Migrations
Marin, O., Valiente, M., Ge, X., & Tsai, L.-H. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001834 · Cited by 417 · see citing works
“Reelin is secreted by Cajal-Retzius cells located in the marginal zone, and it binds to two members of the lipoprotein family receptors, VLDLR and ApoER2 (D’Arcangelo et al. 1999; Hiesberger et al. 1999).”
BackgroundReelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway
Niu, S., Renfro, A., Quattrocchi, C. C., Sheldon, M., & D'Arcangelo, G. (2004) · Neuron · doi:10.1016/s0896-6273(03)00819-5 · Cited by 375 · see citing works
Self-citationReelin Activates Src Family Tyrosine Kinases in Neurons
Bock, H. H., & Herz, J. (2003) · Current Biology · doi:10.1016/s0960-9822(02)01403-3 · Cited by 355 · see citing works
LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction
Weatherbee, S. D., Anderson, K. V., & Niswander, L. A. (2006) · Development · doi:10.1242/dev.02696 · Cited by 351 · see citing works
“Vldlr and Lrp8 (also known as apoER2) are receptors for reelin and are required for normal layering of cortical neurons (D’Arcangelo et al., 1999; Hiesberger et al., 1999; Trommsdorff et al., 1999).”
BackgroundLife is a journey: a genetic look at neocortical development
Gupta, A., Tsai, L., & Wynshaw-Boris, A. J. (2002) · Nature Reviews Genetics · doi:10.1038/nrg799 · Cited by 358 · see citing works
Midkine and pleiotrophin in neural development and cancer
Kadomatsu, K., & Muramatsu, T. (2003) · Cancer Letters · doi:10.1016/s0304-3835(03)00450-6 · Cited by 354 · see citing works
Neuronal migration disorders: from genetic diseases to developmental mechanisms
Gleeson, J. G., & Walsh, C. A. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01607-6 · Cited by 344 · see citing works
Franco, S. J., Martínez‐Garay, I., Gil, C., Harkins-Perry, S. R., & Müller, U. (2011) · Neuron · doi:10.1016/j.neuron.2011.01.003 · Cited by 329 · see citing works
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APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306 · see citing works
Reelin-mediated Signaling Locally Regulates Protein Kinase B/Akt and Glycogen Synthase Kinase 3β
Beffert, U., Morfini, G., Bock, H. H., Reyna, H., Brady, S. T., & Herz, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209205200 · Cited by 306 · see citing works
Heinrich, C., Nitta, N., Flubacher, A., Müller, M., Fahrner, A., Kirsch, M., Freiman, T. M., Suzuki, F., Depaulis, A., Frotscher, M., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5516-05.2006 · Cited by 303 · see citing works
“, 1995), mouse mutants deficient in apolipoprotein E receptor 2 and the very-low-density lipoprotein receptor, as well as mice deficient in the adaptor protein Disabled 1 (Dab1) (Howell et al., 1997; Sheldon et al., 1997; D’Arcangelo et al., 1999; Trommsdorf et al., 1999) all show granule cell migration defects.”
BackgroundXie, Z., Sanada, K., Samuels, B. A., Shih, H. H., & Tsai, L. (2003) · Cell · doi:10.1016/s0092-8674(03)00605-6 · Cited by 305 · see citing works
Reelin modulates NMDA receptor activity in cortical neurons
Chen, Y., Beffert, U., Ertunc, M., Tang, T.-S., Kavalali, E. T., Bezprozvanny, I., & Herz, J. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1951-05.2005 · Cited by 299 · see citing works
“Reelin binding to the very lowdensity lipoprotein (LDL) receptor (Vldlr) and to the apolipoprotein E receptor 2 (Apoer2) on migrating neurons induces tyrosine phosphorylation of Disabled-1 (Dab1), an adaptor protein that interacts with the cytoplasmic domains of both receptors (D’Arcangelo et al., 1999; Hiesberger et…”
BackgroundExpression profiling of epithelial plasticity in tumor progression
Jechlinger, M., Grünert, S., Tamir, I. H., Janda, E., Lüdemann, S. K., Waerner, T., Seither, P., Weith, A., Beug, H., & Kraut, N. (2003) · Oncogene · doi:10.1038/sj.onc.1206887 · Cited by 295 · see citing works
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Fyn Tyrosine Kinase Is a Critical Regulator of Disabled-1 during Brain Development
Arnaud, L., Ballif, B. A., Förster, E., & Cooper, J. A. (2003) · Current Biology · doi:10.1016/s0960-9822(02)01397-0 · Cited by 283 · see citing works
The involvement of Reelin in neurodevelopmental disorders
Folsom, T. D., & Fatemi, S. H. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.08.015 · Cited by 275 · see citing works
“Activation of DAB1 results in multiple effects including activation of a kinase cascade including phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), ultimately leading to the inhibition of glycogen synthase kinase (GSK3β) which normally phosphorylates the microtubule stabilizing protein tau (Figure 1) (…”
BackgroundInfluentialCrk and CrkL adaptor proteins: networks for physiological and pathological signaling
Birge, R. B., Kalodimos, C. G., Inagaki, F., & Tanaka, S. (2009) · Cell Communication and Signaling · doi:10.1186/1478-811x-7-13 · Cited by 272 · see citing works
“Reelin, a secreted glycoprotein that binds to receptors on hippocampal neurons such as ApoER2, VLDLR, and α3β1 integrin, controls cell positioning during adult neurogenesis via Src-dependent tyrosine phosphorylation of the scaffold protein Dab1 [81].”
InfluentialReelin signaling is impaired in autism
Fatemi, S. H., Snow, A. V., Stary, J. M., Araghi-Niknam, M., Reutiman, T. J., Lee, S., Brooks, A. I., & Pearce, D. A. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.12.018 · Cited by 280 · see citing works
How the extracellular matrix shapes neural development
Long, K. R., & Huttner, W. Β. (2019) · Open Biology · doi:10.1098/rsob.180216 · Cited by 263 · see citing works
Proteins of the CNR Family Are Multiple Receptors for Reelin
Senzaki, K., Ogawa, M., & Yagi, T. (1999) · Cell · doi:10.1016/s0092-8674(00)81552-4 · Cited by 272 · see citing works
Disabled‐2 Colocalizes with the LDLR in Clathrin‐Coated Pits and Interacts with AP‐2
Morris, S. M., & Cooper, J. A. (2001) · Traffic · doi:10.1034/j.1600-0854.2001.020206.x · Cited by 263 · see citing works
“LDLRs are known to constitutively recycle through the endocytic pathway, and Reln is internalized into endocytic vesicles when added to tissue culture cells overexpressing its receptors (20).”
BackgroundStructural and Evolutionary Division of Phosphotyrosine Binding (PTB) Domains
Uhlik, M. T., Temple, B., Bencharit, S., Kimple, A. J., Siderovski, D. P., & Johnson, G. L. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.10.038 · Cited by 261 · see citing works
Loukinova, E. B., Ranganathan, S., Kuznetsov, S., Gorlatova, N. V., Migliorini, M. M., Loukinov, D. I., Ulery, P. G., MIKHAILENKO, I. A., Lawrence, D. A., & Strickland, D. K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200427200 · Cited by 260 · see citing works
Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development
Howell, B. W., Herrick, T. M., Hildebrand, J. D., Zhang, Y., & Cooper, J. A. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00608-4 · Cited by 258 · see citing works
“The extracellular domains of the LDLR family proteins apolipoprotein receptor 2 (apoER2) and very low density lipoprotein receptor (VLDLR) bind to a variety of extracellular molecules, including apoE-containing lipoproteins and the Reln protein, which they transport into cells via coated pits [29,30].”
The adaptor molecule Disabled‐2 links the transforming growth factor β receptors to the Smad pathway
Hocevar, B. A., Smine, A., Xu, X., & Howe, P. H. (2001) · The EMBO Journal · doi:10.1093/emboj/20.11.2789 · Cited by 248 · see citing works
Role for Reelin in the Development of Granule Cell Dispersion in Temporal Lobe Epilepsy
Haas, C. A., Dudeck, O., Kirsch, M., Huszka, C., Kann, G., Pollak, S., Zentner, J., & Frotscher, M. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-14-05797.2002 · Cited by 241 · see citing works
“Mice lacking reelin and its lipoprotein receptors apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) as well as mice deficient in the adaptor protein disabled 1 (dab1) show severe migration defects in the neocortex, hippocampus, and cerebellum (Rakic and Caviness, 1995; Howell et al…”
BackgroundReelin signaling directly affects radial glia morphology and biochemical maturation
Hartfuss, E., Förster, E., Bock, H. H., Hack, M. A., Leprince, P., Luque, J. M., Herz, J., Frotscher, M., & Götz, M. (2003) · Development · doi:10.1242/dev.00654 · Cited by 237 · see citing works
“Upon reelin binding to Apoer2/Vldlr receptors the cytosolic adapter protein mouse disabled 1 (Dab1) is phosphorylated by Src family kinases (D’Arcangelo et al., 1999; Howell et al., 1999; Hiesberger et al., 1999; Bock and Herz, 2003; Arnaud et al., 2003) and downstream signaling is thought to affect neuronal migration…”
BackgroundInfluentialReelin glycoprotein: structure, biology and roles in health and disease
Fatemi, S. H. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001613 · Cited by 241 · see citing works
“11 Reelin binds several proteins as likely receptors, including apolipoprotein E receptor 2 (ApoER2), very-low-density lipoprotein receptor (VLDL-R) and α 3 β 1 integrin protein”
BackgroundThe reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2
Stockinger, W., Brandes, C., Fasching, D., Hermann, M., Gotthardt, M., Herz, J., Schneider, W. J., & Nimpf, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004119200 · Cited by 239 · see citing works
The Cells of Cajal-Retzius: Still a Mystery One Century After
Soriano, E., & del Rı́o, J. A. (2005) · Neuron · doi:10.1016/j.neuron.2005.04.019 · Cited by 237 · see citing works
Human Brain Malformations and Their Lessons for Neuronal Migration
Ross, M. E., & Walsh, C. A. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1041 · Cited by 235 · see citing works
Reelin Regulates Neuronal Progenitor Migration in Intact and Epileptic Hippocampus
Gong, C., Wang, T., Huang, H. S., & Parent, J. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3111-06.2007 · Cited by 233 · see citing works
“Reelin binds to the apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) expressed on neurons or radial glia (D’Arcangelo et al., 1999; Hiesberger et al., 1999; Trommsdorff et al., 1999; Luque et al., 2003).”
BackgroundHerz, J. (2001) · Neuron · doi:10.1016/s0896-6273(01)00234-3 · Cited by 233 · see citing works
Gestational Influenza and Bipolar Disorder in Adult Offspring
Parboosing, R., Bao, Y., Shen, L., Schaefer, C. A., & Brown, A. S. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.896 · Cited by 224 · see citing works
Li, Y., Marzolo, M., van Kerkhof, P., Strous, G. J., & Bu, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000490200 · Cited by 229 · see citing works
Groc, L., Choquet, D., Stephenson, F. A., Verrier, D., Manzoni, O. J., & Chavis, P. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1772-07.2007 · Cited by 225 · see citing works
“During postnatal development of the CNS, the dynamic maturation of synaptic contacts participates in the refinement of immature neuronal networks.”
BackgroundThe low-density lipoprotein receptor gene family: a cellular Swiss army knife?
Nykjær, A., & Willnow, T. E. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)02282-1 · Cited by 222 · see citing works
Reelin expression and glycosylation patterns are altered in Alzheimer’s disease
Botella-López, A., Burgaya, F., Gavín, R., García-Ayllón, M. S., Gómez-Tortosa, E., Peña-Casanova, J., Ureña, J. M., Del Río, J. A., Blesa, R., Soriano, E., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601279103 · Cited by 221 · see citing works
Apolipoprotein E receptors: linking brain development and alzheimer's disease
Herz, J., & Beffert, U. (2000) · Nature reviews. Neuroscience · doi:10.1038/35036221 · Cited by 218 · see citing works
Interaction between Reelin and Notch Signaling Regulates Neuronal Migration in the Cerebral Cortex
Hashimoto‐Torii, K., Torii, M., Sarkisian, M. R., Bartley, C. M., Shen, J., Radtke, F., Gridley, T., Šestan, N., & RAKIC, P. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.09.026 · Cited by 216 · see citing works
“Very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor type2 (ApoER2) are canonical Reelin-binding receptors that subsequently activate intracellular Dab1 (Sheldon et al., 1997; Howell et al., 1997, 1999, 2000; Ware et al., 1997; Rice et al., 1998; Trommsdorff et al., 1999; Hiesberger et al., 1999…”
BackgroundDCX, a new mediator of the JNK pathway
Gdalyahu, A., Ghosh, I., Levy, T., Sapir, T., Sapoznik, S., Fishler, Y., Azoulai, D., & Reiner, O. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600079 · Cited by 218 · see citing works
Interaction of reelin signaling and Lis1 in brain development
Assadi, A. H., Zhang, G., Beffert, U., McNeil, R. S., Renfro, A., Niu, S., Quattrocchi, C. C., Antalffy, B. A., Sheldon, M., Armstrong, D. D., et al. (2003) · Nature Genetics · doi:10.1038/ng1257 · Cited by 219 · see citing works
“Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptor”
BackgroundSelf-citationJossin, Y. (2020) · Biomolecules · doi:10.3390/biom10060964 · Cited by 208 · see citing works
Absence of Fyn and Src Causes a Reeler-Like Phenotype
Kuo, G., Arnaud, L., Kronstad-O'Brien, P., & Cooper, J. A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1656-05.2005 · Cited by 200 · see citing works
“Vldr and ApoER2 are receptors that bind to Reelin through their extracellular domains and to Dab1 through their cytoplasmic domains (D’Arcangelo et al., 1999; Hiesberger et al., 1999; Howell et al., 1999b).”
Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice
QIU, S., KORWEK, K., PRATTDAVIS, A., PETERS, M., BERGMAN, M., & WEEBER, E. (2006) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2005.11.001 · Cited by 202 · see citing works
Protein–Protein interactions, cytoskeletal regulation and neuronal migration
Feng, Y., & Walsh, C. A. (2001) · Nature reviews. Neuroscience · doi:10.1038/35077559 · Cited by 205 · see citing works
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Lopera, F., Marino, C., Chandrahas, A. S., O’Hare, M., Villalba-Moreno, N. D., Aguillon, D., Baena, A., Sanchez, J. S., Vila-Castelar, C., Ramirez Gomez, L., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02318-3 · Cited by 192 · see citing works
Segarini, P. R., Nesbitt, J. E., Li, D., Hays, L. G., Yates, J. R., & Carmichael, D. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105180200 · Cited by 200 · see citing works
Costa, E., Davis, J. M., Grayson, D. R., Guidotti, A., Pappas, G. D., & Pesold, C. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0436 · Cited by 197 · see citing works
Receptor Clustering Is Involved in Reelin Signaling
Strasser, V., Fasching, D., Hauser, C., Mayer, H., Bock, H. H., Hiesberger, T., Herz, J., Weeber, E. J., Sweatt, J. D., Pramatarova, A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.1378-1386.2004 · Cited by 193 · see citing works
“essentially as described previously (11, 14).”
BackgroundSekine, K., Kawauchi, T., Kubo, K., Honda, T., Herz, J., Hattori, M., Kinashi, T., & Nakajima, K. (2012) · Neuron · doi:10.1016/j.neuron.2012.07.020 · Cited by 180 · see citing works
“Reelin binds to its receptors, Apo-lipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and induces the phosphorylation of the intracellular adaptor protein disabled homolog 1 (Dab1) in migrating neurons (D’Arcangelo et al., 1999; Hiesberger et al., 1999; Trommsdorff et al., 1999; Rice…”
Ishihara, T., Iino, Y., Mohri, A., Mori, I., Gengyo‐Ando, K., Mitani, S., & Katsura, I. (2002) · Cell · doi:10.1016/s0092-8674(02)00748-1 · Cited by 181 · see citing works
Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus
Qiu, S., Zhao, L. F., Korwek, K. M., & Weeber, E. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2561-06.2006 · Cited by 186 · see citing works
“The developmental lamination of the hippocampus and other cortical structures requires a signaling cascade initiated by reelin and its receptors, apoER2 (apolipoprotein E receptor 2) and VLDLR (very-low-density lipoprotein receptor).”
BackgroundHaines, J. L., Schnetz-Boutaud, N., Schmidt, S., Scott, W. K., Agarwal, A., Postel, E. A., Olson, L., Kenealy, S. J., Hauser, M., Gilbert, J. R., et al. (2006) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.05-0116 · Cited by 189 · see citing works
Arendt, T. (2003) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2003.09.007 · Cited by 188 · see citing works
Rescue of Ataxia and Preplate Splitting by Ectopic Expression of Reelin in reeler Mice
Magdaleno, S. M., Keshvara, L. M., & Curran, T. (2002) · Neuron · doi:10.1016/s0896-6273(02)00582-2 · Cited by 186 · see citing works
Self-citationLRP2/megalin is required for patterning of the ventral telencephalon
Spoelgen, R., Hammes, A., Anzenberger, U., Zechner, D., Andersen, O. M., Jerchow, B., & Willnow, T. E. (2004) · Development · doi:10.1242/dev.01580 · Cited by 175 · see citing works
“…et al., 2001a; Mao et al., 2001b), while apolipoprotein E receptor2 and very low-density lipoprotein receptor function as receptors for Reelin, a signaling factor that controls neuronal migration in the embryonic brain (Trommsdorf et al., 1999; Hiesberger et al., 1999; D’Arcangelo et al., 1999).”
BackgroundTakahashi, S., Sakai, J., Fujino, T., Hattori, H., Zenimaru, Y., Suzuki, J., Miyamori, I., & Yamamoto, T. T. (2004) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.11.200 · Cited by 177 · see citing works
Bacskai, B. J., Xia, M., Strickland, D. K., Rebeck, G. W., & Hyman, B. T. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.200238297 · Cited by 183 · see citing works
Burk, R. F., Hill, K. E., Olson, G. E., Weeber, E. J., Motley, A. K., Winfrey, V. P., & Austin, L. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1153-07.2007 · Cited by 181 · see citing works
Calcium signaling dysfunction in schizophrenia: a unifying approach
Lidow, M. S. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(03)00203-0 · Cited by 173 · see citing works
de Rouvroit, C. L., & Goffinet, A. M. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00396-3 · Cited by 176 · see citing works
Formation and function of apolipoprotein E-containing lipoproteins in the nervous system.
Vance, J., & Hayashi, H. (2010) · Biochimica et Biophysica Acta · doi:10.1016/j.bbalip.2010.02.007 · Cited by 185 · see citing works
The role of Rho GTPase proteins in CNS neuronal migration
Govek, E., Hatten, M. E., & Aelst, L. V. (2010) · Developmental Neurobiology · doi:10.1002/dneu.20850 · Cited by 172 · see citing works
“When DAB1 is tyrosine phosphorylated, it provides a scaffold for signaling complexes, including Crk and CrkL adaptors, and CrkII links phosphorylated DAB1 to the Rac GEF DOCK180/DOCK1 (Ballif et al., 2004; Chen et al., 2004; Huang et al., 2004).”
BackgroundInfluentialReelin and Stk25 Have Opposing Roles in Neuronal Polarization and Dendritic Golgi Deployment
Matsuki, T., Matthews, R. T., Cooper, J. A., van der Brug, M. P., Cookson, M., Hardy, J., Olson, E. C., & Howell, B. W. (2010) · Cell · doi:10.1016/j.cell.2010.10.029 · Cited by 166 · see citing works
“Genetic and biochemical studies have shown that it regulates a signal transduction pathway requiring the ApoE receptors ApoER2 and VLDLR (D’Arcangelo et al., 1999; Hiesberger et al., 1999; Trommsdorff et al., 1999), the cytoplasmic adaptor protein Dab1 (Howell et al., 2000), and Src family kinases (Arnaud et al., 2003…”
BackgroundInfluentialDAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing
Hoe, H.-S., Tran, T. S., Matsuoka, Y., Howell, B. W., & Rebeck, G. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602162200 · Cited by 174 · see citing works
ROCK and Rho: Biochemistry and Neuronal Functions of Rho-Associated Protein Kinases
Schmandke, A., Schmandke, A., & Strittmatter, S. M. (2007) · The Neuroscientist · doi:10.1177/1073858407303611 · Cited by 170 · see citing works
LIS1 and dynein motor function in neuronal migration and developmentPreprint
Wynshaw-Boris, A. J., & Gambello, M. J. (2001) · Genes & Development · doi:10.1101/gad.886801 · Cited by 166 · see citing works
LDL Receptor-Related Protein as a Component of the Midkine Receptor
Muramatsu, H., Zou, K., Sakaguchi, N., Ikematsu, S., Sakuma, S., & Muramatsu, T. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2549 · Cited by 168 · see citing works
Reelin gene alleles and susceptibility to autism spectrum disorders
Zhang, H., Liu, X., Zhang, C., Mundo, E., Macciardi, F. M., Grayson, D. R., Guidotti, A. R., & Holden, J. J. A. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001124 · Cited by 167 · see citing works
“6 Reelin directs cortical layer formation by acting on migrating target cells, such as cortical plate neurons in the cerebral cortex and Purkinje cells in the cerebellum, through its interaction with the adaptor protein dab1”
Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons
Hack, I., Hellwig, S., Junghans, D., Brunne, B., Bock, H. H., Zhao, S., & Frotscher, M. (2007) · Development · doi:10.1242/dev.005447 · Cited by 162 · see citing works
“Neurons migrating radially towards the cortical plate express at least three essential elements of the reelin signaling cascade: the two reelin receptors Vldlr (very low density lipoprotein receptor) and ApoER2 (apolipoprotein E receptor 2; also known as Lrp8 – Mouse Genome Informatics) (D’Arcangelo et al., 1999; Trom…”
BackgroundGene clustering by Latent Semantic Indexing of MEDLINE abstracts
Homayouni, R., Heinrich, K. E., Wei, L., & Berry, M. W. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth464 · Cited by 163 · see citing works
“Apolipoprotein E blocks the interaction of Reelin with its receptors and is also considered a risk factor for late-onset AD ( D'Arcangelo et al., 1999; Selkoe, 2001).”
BackgroundSelf-citationSanada, K., Gupta, A., & Tsai, L. (2004) · Neuron · doi:10.1016/s0896-6273(04)00222-3 · Cited by 166 · see citing works
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · see citing works
Tau and transgenic animal models
Götz, J. (2001) · Brain Research Reviews · doi:10.1016/s0165-0173(01)00055-8 · Cited by 161 · see citing works
Supèr, H. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.6.602 · Cited by 160 · see citing works
“Reelin-receptors and Reelin-associated signaling transduction proteins (Howell et al., 1997; Sheldon et al., 1997; D’Arcangelo et al., 1999; Hiesberger et al., 1999; Senzaki et al., 1999), the mechanisms by which CR cells participate in neuronal migration have not been elucidated.”
BackgroundLi, Y., Lü, W., Marzolo, M., & Bu, G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101589200 · Cited by 163 · see citing works
Low-Density Lipoprotein Receptor Family
Bu, G., Li, Y., & Cam, J. A. (2001) · Molecular Neurobiology · doi:10.1385/mn:23:1:53 · Cited by 157 · see citing works
“Subsequently, Reelin was demonstrated to be a ligand for both VLDLR and apoER2 (47,48).”
BackgroundRodríguez, M. Á., Pesold, C., Liu, W. S., Kriho, V., Guidotti, A., Pappas, G. D., & Costa, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050589797 · Cited by 178 · see citing works
- 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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