Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system.
Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1-/- mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters. We also found hypomyelination in the peripheral nervous system (PNS) of Nrd1-/- mice. Neuron-specific overexpression of NRDc induced hypermyelination, indicating that the level of neuronal NRDc regulates myelin thickness. Consistent with these findings, Nrd1-/- mice had impaired motor activities and cognitive deficits. Furthermore, NRDc enhanced ectodomain shedding of neuregulin1 (NRG1), which is a master regulator of myelination in the PNS. On the basis of these data, we propose that NRDc regulates axonal maturation and myelination in the CNS and PNS, in part, through the modulation of NRG1 shedding.
Ohno
Mikiko
M
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Hiraoka
Yoshinori
Y
Matsuoka
Tatsuhiko
T
Tomimoto
Hidekazu
H
Takao
Keizo
K
Miyakawa
Tsuyoshi
T
Oshima
Naoko
N
Kiyonari
Hiroshi
H
Kimura
Takeshi
T
Kita
Toru
T
Nishi
Eiichiro
E
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D061085:Agenesis of Corpus Callosum; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001369:Axons / Q000473:pathology / Q000502:physiology*; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D003337:Corpus Callosum / Q000502:physiology*; D003712:Dendrites / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000002:abnormalities / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D020890:Neuregulin-1 / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D012584:Sciatic Nerve / Q000002:abnormalities / Q000502:physiology*; D013131:Spine / Q000002:abnormalities / Q000502:physiology*
D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D008666:Metalloendopeptidases; C087976:nardilysin; D000072198:ADAM17 Protein