Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors

Yasui, Norio; Nogi, Terukazu; Kitao, Tomoe; Nakano, Yoshimi; Hattori, Mitsuharu; Takagi, Junichi

doi:10.1073/pnas.0700438104

Cited by 74 publications

(88 citation statements)

References 49 publications

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“…of cell aggregates was observed at a level similar to the level observed in the mock control when 2A-Reelin was used; 2A-Reelin is the product of a point mutation of Reelin that contains two mutant lysine residues, which prevents binding of Reelin to its receptors (19) (Fig. 1 C, C′, and D and Fig.…”

Section: Resultsmentioning

confidence: 80%

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Matsunaga

Noda

Murakawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin-dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin-mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin-mediated adhesion is important for correct positioning of the neurons during neocortical development.T he mammalian neocortex is highly organized into six neuronal layers. This laminar structure is responsible for the complex motor, sensory, and cognitive functions of the mammalian brain (1). Neuronal migration plays an important role in the establishment of this layered structure. Cortical neurons are generated within the ventricular zone (VZ) or subventricular zone (SVZ), and migrate along radial fibers toward the pial surface. Newly born excitatory neurons migrate radially into the cortical plate (CP) past the neurons born earlier, resulting in a birth date-dependent "inside-out" alignment of the neurons in the CP (2-4).Reelin is a glycoprotein that is secreted by the Cajal-Retzius cells in the marginal zone (MZ) of the cortex during neocortical development (5-7). This glycoprotein is essential for establishment of the aforementioned birth date-dependent layered structure of the neocortex, because the CP neurons show an almost inverted alignment in the neocortex of the Reelindeficient, reeler mice. In addition, neurons born at the same time tend to be distributed broadly and not to form clear layers in the reeler cortex (8, 9). Although extensive studies, including at the molecular level, have been conducted to determine the role of Reelin in neuronal migration i...

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Section: Resultsmentioning

confidence: 80%

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Matsunaga

Noda

Murakawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…A reciprocal effect is also conceivable, with A␤ peptides promoting Reelin aggregation. Support for this hypothesis has been recently provided by Botella-Ló pez et al (2010), demonstrating that amyloid-␤ peptides can alter Reelin processing and glycosylation, critical modifications demonstrated to be required for proper Reelin-mediated signaling (Lambert de Rouvroit et al, 1999;Koch et al, 2002;Jossin et al, 2007) and potentially involved in abnormal oligomerization and aggregation of Reelin (Utsunomiya-Tate et al, 2000;Kubo et al, 2002;Yasui et al, 2007).…”

Section: Discussionmentioning

confidence: 94%

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Kocherhans¹,

Madhusudan²,

Doehner³

et al. 2010

Journal of Neuroscience

108

102

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In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-␤ plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-␤ peptides, the significant increase in number and size of amyloid-␤ plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-␤ plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-␤ plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-␤ plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-␤ deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

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“…In some in vitro studies, it has been reported that three to six (R3-6) repeat fragments of the EGF-like domain can bind to ApoER2 and VLDLR, which are involved in neuron signal transduction (Jossin et al, 2004;Chameau et al, 2009). Moreover, addition of the repeat 5-6 fragments is sufficient to induce phosphorylation of Dab1 (Yasui et al, 2007), which is an "adapter molecule" that transduces the signal to the next molecule in the cytosol and is responsible for triggering of the reelin intracellular signaling pathway. These studies indicate that this risk allele maybe within a regulatory element.…”

Section: Discussionmentioning

confidence: 99%

A new single-nucleotide mutation (rs362719) of the reelin (RELN) gene associated with schizophrenia in female Chinese Han

Wj¹,

Rf²,

Ys³

et al. 2011

Genet. Mol. Res.

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ABSTRACT.Reelin is an extracellular signaling protein that plays an important role in the development of the central nervous system. Postmortem studies have shown lower reelin protein levels in the brains of patients with schizophrenia and bipolar disorder compared with controls. Genetic studies have also shown that mutations in the reelin gene (RELN) increase the risk for schizophrenia and bipolar disorder. We evaluated whether an RELN gene variant, rs362719, which has been associated with increased susceptibility to bipolar disorder, is also associated with susceptibility to schizophrenia. We included 405 Chinese Han schizophrenia patients and 390 controls in our study. The polymorphism was genotyped by PCR and RFLP methods. We found a significant difference in allele frequency distribution (P < 0.05) between schizophrenia patients and controls. The frequency of the A allele was significantly higher in schizophrenia patients than in healthy controls. The effect of SNP rs362719 on allele distribution was significant in female (P < 0.05) but not in male participants (P = 0.473). Besides the gender factor, demographic and clinical characteristics of the rs362719 genotype groups were also analyzed using the chi-square test, but no significant differences were found. We conclude that rs362719 of the RELN gene is associated with susceptibility to schizophrenia in Chinese Han, possibly through a gender-specific mechanism. Further studies will be needed to confirm this genetic risk factor for schizophrenia.

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Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors

Cited by 74 publications

References 49 publications

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Reduced Reelin Expression Accelerates Amyloid- Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

A new single-nucleotide mutation (rs362719) of the reelin (RELN) gene associated with schizophrenia in female Chinese Han

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