Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning

@article{Tinnes2011EpileptiformAI,
  title={Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning},
  author={Stefanie Tinnes and Michael K. E. Sch{\"a}fer and Armin Flubacher and Gert M{\"u}nzner and Michael Frotscher and Carola A. Haas},
  journal={The FASEB Journal},
  year={2011},
  volume={25},
  pages={1002 - 1013}
}
The extracellular matrix protein Reelin is an essential regulator of neuronal migration and lamination in the developing and mature brain. Lack of Reelin causes severe disturbances in cerebral layering, such as the reeler phenotype and granule cell dispersion in temporal lobe epilepsy. Reelin is synthesized and secreted by Cajal‐Retzius cells and GABAergic interneurons, and its function depends on proteolytic cleavage after secretion. The mechanisms regulating these processes are largely… 
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TIMP‐1 inhibits the proteolytic processing of Reelin in experimental epilepsy
TLDR
Evidence is presented that epileptic conditions inhibit MMP activity by up‐regulation of endogenous TIMP‐1, which in turn leads to extracellular accumulation of uncleaved and inactive Reelin and thereby to GCD, similar to that observed after KA treatment.
Serine 1283 in extracellular matrix glycoprotein Reelin is crucial for Reelin’s function in brain development
TLDR
The results indicate that ecto-phosphorylation at serine 1283 rather than proteolytic processing of adhesion molecules by Reelin plays an important role in Reelin functions.
Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation
Impaired reelin processing and secretion by Cajal–Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy
TLDR
GCD results from abnormal reelin processing in Cajal–Retzius cells under the control of BDNF, suggesting that production of truncated reelin in KA‐treated hippocampus is activity‐dependent and regulated by BDNF.
Reelin Is Required for Maintenance of Granule Cell Lamination in the Healthy and Epileptic Hippocampus
TLDR
It is demonstrated that normotopic position of Reelin is essential for the maintenance of GC lamination in the dentate gyrus and that GCD is the result of a local Reelin deficiency.
Molecular and Cellular Mechanisms of Reelin Signaling in the Adult Hippocampus
TLDR
It is reported that reelin is cleaved between EGF-like repeats 6-7 (R6-7) by tissue plasminogen activator (tPA) under cell-free conditions, and forskolin treatment resulted in altered processing of reelin in hippocampal area CA1, an effect not observed in tPA knockouts.
Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice
TLDR
Reelin knock-in mice are generated in which the key cleavage site of Reelin was abolished by mutation and the cleavage was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice, presenting the first direct evidence of the physiological importance ofReelin cleavage.
Seizure-Induced Motility of Differentiated Dentate Granule Cells Is Prevented by the Central Reelin Fragment
TLDR
It is suggested that GCD formation is indeed triggered by a loss of Reelin in hilar interneurons, as observed in vivo.
Regulation of Reelin functions by specific proteolytic processing in the brain.
TLDR
This review focuses on Reelin proteolytic processing and review its potential physiological roles and suggested molecular mechanisms underpinning Reelin function remain unclear.
Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice
TLDR
Reelin knock-in mice are generated in which the key cleavage site of Reelin was abolished by mutation, and the cleavage was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice, presenting the first direct evidence of the physiological importance ofReelin cleavage.
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References

SHOWING 1-10 OF 45 REFERENCES
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TLDR
It is shown that the Reelin signaling pathway is essential for the correct positioning of human hippocampal neurons and that a Reelin deficiency is involved in the pathological changes associated with epilepsy.
Exogenous reelin prevents granule cell dispersion in experimental epilepsy
Impaired reelin processing and secretion by Cajal–Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy
TLDR
GCD results from abnormal reelin processing in Cajal–Retzius cells under the control of BDNF, suggesting that production of truncated reelin in KA‐treated hippocampus is activity‐dependent and regulated by BDNF.
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TLDR
It is shown that a decreased expression of reelin mRNA by hippocampal Cajal–Retzius cells correlates with the extent of migration defects in the dentate gyrus of patients with temporal lobe epilepsy, suggesting that reelin is required for normal neuronal lamination in humans, and that deficient reelin expression may be involved in migration defects associated withporal lobe epilepsy.
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TLDR
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TLDR
It is shown that in epilepsy reelin dysfunction causes GCD development and that reelin is important for the maintenance of layered structures in the adult brain.
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TLDR
It is proposed that processing by end-migration neurons is required in tissue to release the central fragment that diffuses locally and signals to target cells, whereas, in vitro, all Reelin forms have indiscriminate access to cells, so that cleavage is not necessary for signaling.
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TLDR
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TLDR
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