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

Authors :
Hitomi Tsuiji
Himari Ogino
Tomofumi Shigenobu
Takao Kohno
Eisuke Okugawa
Yuko Yamakage
Mitsuharu Hattori
Hisashi Oishi
Source :
Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020), Scientific Reports
Publication Year :
2020
Publisher :
Nature Publishing Group, 2020.

Abstract

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 importancein vivois 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.

Details

Language :
English
ISSN :
20452322
Volume :
10
Issue :
1
Database :
OpenAIRE
Journal :
Scientific Reports
Accession number :
edsair.doi.dedup.....b150d68d8ddbc8e811d1f5bf32232c26
Full Text :
https://doi.org/10.1038/s41598-020-61380-w