2-B-P-027 〇大野 美紀子¹、江角 重行²、大林 徹也³、西 清人¹、西 英一郎¹ Ohno Mikiko¹, Shigeyuki Esumi², Tetsuya Obayashi³, Kiyoto Nishi¹, Eiichiro Nishi^{1 1}滋賀医科大・医、²熊本大・医・形態構築学分野、³鳥取大・医・研究推進機構 先進医療研究センター ¹Dept. of Pharmacology. Shiga U. Med.Sci., ²Dept. of Anatomy and Neurobiology, Kumamoto U, ³Org. Research initiative and promotion, Tottori U. Nardilysin (N-Arginine Dibasic Convertase: NRDC) is a metalloendopeptidase belonging to the M16 family, which enzymatically cleaves on the N-terminal side of the arginine residue at a dibasic site. Although prior studies identified Dynorphin-A, somatostatin-28, α-neoendorphin, and glucagon as in vitro substrates for NRDC, but its in vivo substrates remain elusive.
We generated and analyzed whole body knockout mouse of NRDC, which displayed impaired axonal maturation and hypomyelination in the CNS. These findings were attributed to reduced ectodomain shedding of neuregulin 1 (NRG1), a myelination promoting factor, because NRDC enhances ectodomain shedding of NRG1 via the complex formation with ADAM17 or BACE1.
To elucidate the in vivo role of NRDC enzymatic activity, we generated NRDC E>A knock-in mice, where the enzymatically active glutamate (E) was substituted by alanine (A). Adult NRDC E>A KI/KI mice showed growth retardation, aberrant behavior, and epileptiform vertical head movements which are reminiscent of NRDC-KO mice. However, they lacked certain traits seen in NRDC-KO mice, such as ventricular enlargement and hypomyelination. Additionally, we found no decrease in NRG1 shedding in the brains of NRDC E>A KI/KI mice, which was observed in NRDC-KO mice. These results indicated the strong link between myelination and NRDC-induced NRG1 shedding, at the same time, suggested that there are unknown underlying mechanisms by which NRDC enzymatic activity regulates behaviors.