PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination

Jun-Dal Kim; Kyung-Eui Park; Junji Ishida; Koichiro Kako; Juri Hamada; Shuichi Kani; Miki Takeuchi; Kana Namiki; Hajime Fukui; Shigetomo Fukuhara; Masahiko Hibi; Makoto Kobayashi; Yasunori Kanaho; Yoshitoshi Kasuya; Naoki Mochizuki; Akiyoshi Fukamizu

doi:10.1126/sciadv.1500615

PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination

Sci Adv. 2015 Dec 4;1(11):e1500615. doi: 10.1126/sciadv.1500615. eCollection 2015 Dec.

Authors

Affiliations

¹ Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
² Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8572, Japan.
³ Laboratory for Vertebrate Axis Formation, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.
⁴ Laboratory of Organogenesis and Organ Function, Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi 464-8601, Japan. ; Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.
⁵ Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba 260-8670, Japan.
⁶ Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
⁷ Laboratory for Vertebrate Axis Formation, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan. ; Laboratory of Organogenesis and Organ Function, Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi 464-8601, Japan.
⁸ Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.
⁹ Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.
¹⁰ Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan. ; AMED-CREST, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.
¹¹ Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan. ; Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8572, Japan. ; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.

Abstract

The development of vertebrate neurons requires a change in membrane phosphatidylcholine (PC) metabolism. Although PC hydrolysis is essential for enhanced axonal outgrowth mediated by phospholipase D (PLD), less is known about the determinants of PC metabolism on dendritic arborization. We show that protein arginine methyltransferase 8 (PRMT8) acts as a phospholipase that directly hydrolyzes PC, generating choline and phosphatidic acid. We found that PRMT8 knockout mice (prmt8 (-/-)) displayed abnormal motor behaviors, including hindlimb clasping and hyperactivity. Moreover, prmt8 (-/-) mice and TALEN-induced zebrafish prmt8 mutants and morphants showed abnormal phenotypes, including the development of dendritic trees in Purkinje cells and altered cerebellar structure. Choline and acetylcholine levels were significantly decreased, whereas PC levels were increased, in the cerebellum of prmt8 (-/-) mice. Our findings suggest that PRMT8 acts both as an arginine methyltransferase and as a PC-hydrolyzing PLD that is essential for proper neurological functions.

Keywords: neurology; vertebrates.