Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders

Sakai, Kaori; Shoji, Hirotaka; Kohno, Takao; Miyakawa, Tsuyoshi; Hattori, Mitsuharu

doi:10.1038/srep28636

Cited by 37 publications

(38 citation statements)

References 60 publications

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“…Third, the methylation pattern at the reelin gene promoter is different is ASD and control post-mortem brains [130]. Fourth, mice lacking the C-terminal region of reelin exhibit behavioral abnormalities related to ASD [131]; Fifth, the reeler ( rl −/− ) mouse, a spontaneously arising mutant mouse, displays several ASD-like morphological and behavioral traits [132, 133]. Sixth, cortical disorganization has been reported in reelin-deficient mice and in ASD patients [74, 134].…”

Section: Possible Mechanisms Of Developmental Neurotoxicity Of Traffimentioning

confidence: 99%

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

Costa

Chang

Cole

2017

Curr Envir Health Rpt

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Purpose of Review Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Recent findings Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity, and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication, and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Summary Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions, are certainly warranted.

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Section: Possible Mechanisms Of Developmental Neurotoxicity Of Traffimentioning

confidence: 99%

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

Costa

Chang

Cole

2017

Curr Envir Health Rpt

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“…4H, white bars). This result was unexpected because a similar phenomenon was reported in the mice with attenuated Reelin signaling 14,37,38 but not in ADAMTS-3 KO mice 12 .…”

Section: Some Hippocampal Neurons Were Ectopically Located In Ki/ki Mmentioning

confidence: 62%

“…Mice with attenuated Reelin signaling often exhibit behavioral abnormalities 38,55 . It would be interesting to test if the PA-DV mutations could correct or improve these abnormalities.…”

Section: Second Bothmentioning

confidence: 99%

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

Okugawa

Ogino

Shigenobu

et al. 2020

Preprint

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Reelin is a secreted protein that plays versatile roles in neuronal development and function, and hypoactivity of Reelin is implicated in many neuropsychiatric disorders. The strength of Reelin signaling is regulated by proteolytic processing, but its importance in vivo is not yet fully understood. Here, we generated Reelin knock-in (PA-DV KI) mice in which the key cleavage site of Reelin was abolished by mutation. As expected, the cleavage of Reelin was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice. The amount of Dab1, whose degradation is induced by Reelin signaling, decreased in these tissues, indicating that the signaling strength of Reelin was augmented. The brains of PA-DV KI mice were largely structurally normal, but unexpectedly, the hippocampal layer was disturbed. This phenotype was ameliorated in hemizygote PA-DV KI mice, indicating that excess Reelin signaling is detrimental to hippocampal layer formation. The neuronal dendrites of PA-DV KI mice had more branches and were elongated compared to wild-type mice. These results present the first direct evidence of the physiological importance of Reelin cleavage and suggest that inhibition of Reelin cleavage would counteract neuropsychiatric disorders without causing severe systemic side effects.

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“…This mutant carries a short C-terminal deletion of RELN protein. Studies using multiple mutant mice have revealed that C-terminal region domain (CTR) is important for secretion, proteolytic cleavage, receptor binding, activation of downstream signaling, resulting in abnormalities in brain morphogenesis and behavior (D'Arcangelo et al, 1997;de Bergeyck et al, 1997;Nakano et al, 2007;Kohno et al, 2015;Nakamura et al, 2016;Sakai et al, 2016). Using genetic and biochemical analyses, we have demonstrated that the C-terminal deletion resulted in differential binding of RELN to its receptors; truncated RELN fails to bind to VLDLR but binds normally to APOER2 (Ha et al, 2017).…”

Section: Introductionmentioning

confidence: 89%

Reelin Mediates Hippocampal Cajal-Retzius Cell Positioning and Infrapyramidal Blade Morphogenesis

Ha¹,

Tripathi²,

Daza³

et al. 2019

Preprint

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We have previously described hypomorphic reelin (Reln) mutant mice, Reln CTRdel , in which the morphology of the dentate gyrus is distinct from that seen in reeler mice. In the Reln CTRdel mutant the infrapyramidal blade of the dentate gyrus fails to extend, while the suprapyramidal blade forms with a relatively compact granule neuron layer. The distribution of Cajal-Retzius cells in the dentate gyrus was aberrant; Cajal-Retzius neurons were increased in the suprapyramidal blade, but were greatly reduced along the subpial surface of the prospective infrapyramidal blade. We also observed multiple abnormalities of the fimbriodentate junction. Firstly, progenitor cells were distributed abnormally; the "neurogenic cluster" at the fimbriodentate junction was absent, lacking the normal accumulation of Tbr2-positive intermediate progenitors. However, the number of dividing cells in the dentate gyrus was not generally decreased. Secondly, a defect of secondary glial scaffold formation, limited to the infrapyramidal blade, was observed. The densely radiating glial fibers characteristic of the normal fimbriodentate junction were absent in mutants. These fibers might be required for migration of progenitors, which may account for the failure of neurogenic cluster formation. These findings suggest the importance of the secondary scaffold and neurogenic cluster of the fimbriodentate junction in morphogenesis of the mammalian dentate gyrus. Our study provides direct genetic evidence showing that normal RELN function is required for Cajal-Retzius cell positioning in the dentate gyrus, and for formation of the fimbriodentate junction to promote infrapyramidal blade extension.

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Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders

Cited by 37 publications

References 60 publications

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

Reelin Mediates Hippocampal Cajal-Retzius Cell Positioning and Infrapyramidal Blade Morphogenesis

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