Reelin Is a Ligand for Lipoprotein Receptors

D’Arcangelo, Gabriella; Homayouni, Ramin; Keshvara, Lakhu; Rice, Dennis S.; Sheldon, Michael; Curran, Tom

doi:10.1016/s0896-6273(00)80860-0

Cited by 747 publications

(623 citation statements)

References 46 publications

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“…This hypothesis is supported by studies in transgenic animals showing ectopic accumulations of Dab1 in Reelin-, ApoER2-, and VLDLR-deficient mice (Rice and Curran, 2001;Trommsdorff et al, 1999). In-vitro studies showed that internalization of Reelin-ApoER2 complexes is required for endocytosis and proteasomal degradation of Dab1 (Bock et al, 2004;D'Arcangelo et al, 1999). A direct role of Reelin in APP processing is demonstrated by the increased co-immunoprecipitation of Dab1 with ApoER2 and APP and decreased Aβ production (Hoe et al, 2006a), indicating that reduced Reelin levels might favor the production of neurotoxic Aβ species.…”

Section: Discussionmentioning

confidence: 81%

Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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Age-related accumulation of Reelin in amyloid-like deposits Abstract Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD. ABSTRACTAccumulating evidence suggest that alterations in Reelin-mediated signalling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits.These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Aβ species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.3

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Section: Discussionmentioning

confidence: 81%

Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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“…(27,(31)(32)(33) LRP8, as one of the cell-surface receptors for Reelin, functions as an important regulator of neuron migration in brain development. (34,35) Reelin signals through LRP8 or through very-low-density lipoprotein receptor (VLDLR), induces the interaction between LRP8 and adaptor protein Disabled-1 (Dab1) and tyrosine phosphorylation of Dab1, and further, results in the recruitment of phosphatidylinositol-3-kinase (PI3K) and GSK3b. (34,(36)(37)(38) Interaction between LRP8 and Reelin also initiates internalization of Reelin in the clathrin-mediated endocytosis pathway.…”

Section: Introductionmentioning

confidence: 99%

“…(34,35) Reelin signals through LRP8 or through very-low-density lipoprotein receptor (VLDLR), induces the interaction between LRP8 and adaptor protein Disabled-1 (Dab1) and tyrosine phosphorylation of Dab1, and further, results in the recruitment of phosphatidylinositol-3-kinase (PI3K) and GSK3b. (34,(36)(37)(38) Interaction between LRP8 and Reelin also initiates internalization of Reelin in the clathrin-mediated endocytosis pathway. (39) LRP8 single-knockout mice were grossly normal, but showed reduced male fertility and suffered accelerated cell death during normal aging 4,35 ; LRP8 and VLDLR double-knockout mice displayed disorganized neurons, and cortical lamination was affected in brain development.…”

Section: Introductionmentioning

confidence: 99%

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

Zhang

et al. 2012

Journal of Bone and Mineral Research

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The Wnt/b-catenin signaling pathway plays a pivotal role in regulating osteoblast differentiation and bone formation. Here, we identify low-density lipoprotein (LDL) receptor-related protein 8 (LRP8) as a positive regulator of Wnt/b-catenin signaling. In a small interfering RNA (siRNA) screen, LRP8 was shown to be required for Wnt/b-catenin-induced transcriptional reporter activity. We found that ectopic expression of LRP8 increased Wnt-induced transcriptional responses, and promoted Wnt-induced b-catenin accumulation. Moreover, knockdown of LRP8 resulted in a decrease in b-catenin levels and suppression of Wnt/b-catenin-induced Axin2 transcription. Functional studies in KS483 osteoprogenitor cells showed that LRP8 depletion resulted in impaired activation of endogenous Wnt-induced genes and decreased osteoblast differentiation and mineralization, whereas LRP8 ectopic expression had the opposite effect. These results identify LRP8 as a novel positive factor of canonical Wnt signaling pathway and show its involvement in Wnt-induced osteoblast differentiation. ß

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“…39 Reelin serves a dual purpose in the mammalian brain: it is crucial to the correct cytoarchitecture of laminated structures during embryonic development 18,40 and modulates dendritic growth and synaptic plasticity at post-natal and adult stages. 41,42 These activities are, at least in part, mediated by binding to apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), [43][44][45] resulting in phosphorylation of the intracellular adaptor protein protein disabled homolog 1 (DAB1). [46][47][48] Phosphorylated DAB1 activates several different signaling pathways involved in formation and plasticity of neuronal networks (for review, see ref.…”

mentioning

confidence: 99%

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Dazzo

Fanciulli²,

Serioli

et al. 2015

The American Journal of Human Genetics

106

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Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.Temporal-lobe epilepsy is the most common type of focal epilepsy. It is sometimes associated with structural brain lesions, but genetic forms have also been described. Familial temporal-lobe epilepsy comprises two genetically distinct syndromes: familial mesial temporal-lobe epilepsy (FMTLE [MIM: 611630]) 1 and autosomal-dominant lateral temporal epilepsy (ADLTE [MIM: 600512]), also named autosomal-dominant partial epilepsy with auditory features (ADPEAF). 2 ADLTE is a well-defined epileptic syndrome clinically characterized by focal seizures with prominent auditory and/or aphasic symptoms, normal brain MRI, and relatively benign evolution. 2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) 4-6 in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.LGI1 is expressed mainly in neurons, particularly in the neocortex and limbic regions, 4,9 and its protein product, LGI1, is secreted. 9 LGI1 has been implicated in the transmission of K þ and AMPA synaptic currents 10,11 and in the regulation of post-natal maturation of cortical excitatory synapses and dendrite pruning. 12 However, it is not known which of these functions underlies ADLTE. Identification of additional genes whose mutations cause ADLTE will help to clarify the pathoge...

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Reelin Is a Ligand for Lipoprotein Receptors

Cited by 747 publications

References 46 publications

Age-related accumulation of Reelin in amyloid-like deposits

Age-related accumulation of Reelin in amyloid-like deposits

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

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