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New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis

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Abstract

Our understanding of the physiological relevance of unique Damage-induced neuronal endopeptidase (DINE) [also termed Endothelin-converting enzyme-like 1 (ECEL1)] has recently expanded. DINE/ECEL1 is a type II membrane-bound metalloprotease, belonging to a family including the neprilysin (NEP) and endothelin-converting enzyme (ECE). The family members degrade and/or process peptides such as amyloid β and big-endothelins, which are closely associated with pathological conditions. Similar to NEP and ECE, DINE has been expected to play an important role in injured neurons as well as in developing neurons, because of its remarkable transcriptional response to neuronal insults and predominant neuronal expression from the embryonic stage. However, the physiological significance of DINE has long remained elusive. In the last decade, a series of genetically manipulated mice have driven research progress to elucidate the physiological aspects of DINE. The mice ablating Dine fail to arborize the embryonic motor axons in some subsets of muscles, including the respiratory muscles, and die immediately after birth. The abnormal phenotype of motor axons is also caused by one amino acid exchanges of DINE/ECEL1, which are responsible for distal arthrogryposis type 5 in a group of human congenital movement disorders. Furthermore, the mature Dine-deficient mice in which the lethality is rescued by genetic manipulation have shown the involvement of DINE in central nervous system regeneration. Here we describe recent research advances that DINE-mediated proteolytic processes are critical for nerve development, regeneration and pathogenesis, and discuss the future potential for DINE as a therapeutic target for axonal degeneration/disorder.

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Acknowledgements

We sincerely thank Professor Anthony J. Turner for his fruitful and warmest advice on this study. This work was financially supported by the Japan Society for the Promotion of Science KAKENHI Grant Number 18K15379 (K.N.), KAKENHI Grant Number 18H02524 (S.K.-S.), KAKENHI Grant Number 16H05117 and 17H05743 (H.K.), Japan Foundation for Applied Enzymology (H.K.), Takeda Science Foundation (S.K.-S) and the 24th General Assembly of the Japanese Association of Medical Sciences (S.K.-S.).

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  1. Department of Functional Anatomy and Neuroscience, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Sumiko Kiryu-Seo & Hiroshi Kiyama

  2. Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, 351-0198, Japan

    Kenichi Nagata & Takaomi C. Saido

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  1. Sumiko Kiryu-Seo
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Special issue: In honor of Prof. Anthony J. Turner.

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Kiryu-Seo, S., Nagata, K., Saido, T.C. et al. New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis. Neurochem Res 44, 1279–1288 (2019). https://doi.org/10.1007/s11064-018-2665-x

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