Reelin receptors ApoER2 and VLDLR are expressed in distinct spatiotemporal patterns in developing mouse cerebral cortex

Hirota, Yuki; Kubo, Ken Ichiro; Katayama, Kei‐ichi; Honda, Takao; Fujino, Takahiro; Yamamoto, Tokuo; Nakajima, Kazunori

doi:10.1002/cne.23691

Cited by 50 publications

(58 citation statements)

References 47 publications

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“…Further studies will be necessary to specify the involvement of the reelin receptors ApoER2 and VLDLR, which were found previously to have specific functional roles (Zhao et al, 2006;Hack et al, 2007;Zhao and Frotscher, 2010) and distinct spatiotemporal expression patterns (Hirota et al, 2015).…”

Section: S3ementioning

confidence: 93%

“…Since the neurons always migrate towards the reelin-containing zones, reelin has been proposed to act as a chemoattractive factor for radially migrating neurons (Caffrey et al, 2014). Conversely, reelin has been suggested to be a stop or detachment signal because the MZ, which is enriched in reelin, is almost cell-free in wild-type mice, but is invaded by numerous neurons in the reeler mutant (Frotscher, 1998;Hack et al, 2007;Chai et al, 2009;Zhao and Frotscher, 2010;Hirota et al, 2015). By binding to VLDLR or integrin receptors on the leading processes, reelin in the MZ seems to arrest migrating neurons (Anton et al, 1999;Dulabon et al, 2000;Sanada et al, 2004;Schmid et al, 2005;Hack et al, 2007;Chai et al, 2009;Sekine et al, 2012;Hirota et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Reelin and cofilin cooperate during the migration of cortical neurons: A quantitative morphological analysis

et al. 2016

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In reeler mutant mice, which are deficient in reelin (Reln), the lamination of the cerebral cortex is disrupted. Reelin signaling induces phosphorylation of LIM kinase 1, which phosphorylates the actin-depolymerizing protein cofilin in migrating neurons. Conditional cofilin mutants show neuronal migration defects. Thus, both reelin and cofilin are indispensable during cortical development. To analyze the effects of cofilin phosphorylation on neuronal migration we used in utero electroporation to transfect E14.5 wild-type cortical neurons with pCAG-EGFP plasmids encoding either a nonphosphorylatable form of cofilin 1 (cofilin S3A ), a pseudophosphorylated form (cofilin S3E ) or wild-type cofilin 1 (cofilin WT ). Wild-type controls and reeler neurons were transfected with pCAG-EGFP. Real-time microscopy and histological analyses revealed that overexpression of cofilin WT and both phosphomutants induced migration defects and morphological abnormalities of cortical neurons. Of note, reeler neurons and cofilin S3A -and cofilin S3E -transfected neurons showed aberrant backward migration towards the ventricular zone. Overexpression of cofilin S3E , the pseudophosphorylated form, partially rescued the migration defect of reeler neurons, as did overexpression of Limk1. Collectively, the results indicate that reelin and cofilin cooperate in controlling cytoskeletal dynamics during neuronal migration.

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Section: S3ementioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Reelin and cofilin cooperate during the migration of cortical neurons: A quantitative morphological analysis

et al. 2016

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“…77,78 The VLDL receptor and apoE receptor 2 participate in reelin modulation of neuronal development of cerebral cortex and in reelin-mediated intracellular signaling but not cholesterol transport. 79,80 LDL receptors are most highly expressed in glia and to a lesser extent in neurons. LDL receptor–related protein 1 receptors are more highly expressed in neurons.…”

Section: Role Of Ldl Receptor Family Members In Apoe Delivery Of Cholmentioning

confidence: 99%

Central Nervous System Lipoproteins

Mahley

2016

ATVB

365

172

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ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease.

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“…Reelin is an extracellular matrix glycoprotein that was originally found in the developing brain where it is secreted by Cajal-Retzius neurons in the marginal zone (1, 2). In neurons, Reelin binds to its cognate receptors Apolipoprotein E receptor 2 (Apoer2) and the very low density lipoprotein receptor (Vldlr) on the cell surface (3), thereby promoting tyrosine phosphorylation of the cytoplasmic adaptor protein disabled homolog 1 (Dab1) (1, 4).…”

Section: Introductionmentioning

confidence: 99%

Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation

et al. 2016

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The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to Apolipoprotein E receptor-2 (Apoer2) and very low-density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr−/−) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM-1, VCAM-1 and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing the activity of NF-kB in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

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Reelin receptors ApoER2 and VLDLR are expressed in distinct spatiotemporal patterns in developing mouse cerebral cortex

Cited by 50 publications

References 47 publications

Reelin and cofilin cooperate during the migration of cortical neurons: A quantitative morphological analysis

Reelin and cofilin cooperate during the migration of cortical neurons: A quantitative morphological analysis

Central Nervous System Lipoproteins

Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation

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