Targeted disruption of the mouse protein phosphatase PPM1L gene leads to structural abnormalities in the brain.

• Project/Area Number: 25460353
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Tamura Shinri 東北大学, 加齢医学研究所, 非常勤講師 (20124604)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI TAKAYASU 東北大学, 遺伝子実験センター, 准教授 (10221970)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: プロテインホスファターゼ / 線条体 / 前交連

Outline of Final Research Achievements

To explore function of protein phosphatase PPM1L in vivo, we disrupted the mouse gene by gene targeting. The mutant mice were backcrossed with two different inbred strains (C57/BL6 and CBA), but only homozygous mutant mice on CBA background survived to adulthood. The PPM1L-/- mice showed impaired fine motor coordination and balance in the beam walking assay while Y-maze test did not reveal any specific alterations in their learning memory. Histological analyses revealed that PPM1L-/- mice exhibit morphological abnormalities in the central nerve system including reduction of striatum, corpus callosum and anterior commissure. Histochemical analyses suggest that these structural abnormalities are caused by failure of elongation of axons but not by cell death of neurons. These results suggest that PPM1L may play important role during neural development.

Research Products

• [Journal Article] Regulation of cellular functions by protein phosphatase PPM family members (2015)
  • Author(s): 小林孝安
  • Journal Title: 生化学 Volume: 87 Issue: 5 Pages: 525-530
  • DOI: 10.14952/SEIKAGAKU.2015.870525
  • ISSN: 0037-1017
  • Year and Date: 2015-10-25
• [Journal Article] Mammalian Bcnt/Cfdp1, a potential epigenetic factor characterized by an acidic stretch in the disordered N-terminal and Ser250 phosphorylation in the conserved C-terminal regions (2015)
  • Author(s): Iwashita, S., Suzuki, T., Yasuda, T., Nakashima, K., Sakamoto, T., Kohno, T., Takahashi, I., Kobayashi, T., Ohno-Iwashita, Y., Imajoh-Ohmi, S., Song, S. Y., Dohmae, N.
  • Journal Title: Biosci Rep Volume: 35 Issue: 4 Pages: 1-12
  • DOI: 10.1042/bsr20150111
  • Peer Reviewed / Open Access
• [Journal Article] Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome (2015)
  • Author(s): 竹内陽一、三島英換、他12名
  • Journal Title: J Am Soc Nephrol Volume: 26 Issue: 2 Pages: 271-279
  • DOI: 10.1681/asn.2013091013
  • Peer Reviewed
• [Journal Article] The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts. (2014)
  • Author(s): Matsui, H., Fukuno, N., Kanda, Y., Kantoh, Y., Chida, T., Nagaura, Y., Suzuki, O., Nishitoh, H., Takeda, K., Ichijo, H., Sawada, Y., Sasaki, K., Kobayashi, T. and Tamura, S.
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 10 Pages: 6438-6450
  • DOI: 10.1074/jbc.m113.536300
  • Peer Reviewed / Open Access
• [Journal Article] N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells (2013)
  • Author(s): Chida, T.
  • Journal Title: Biochem J Volume: 449 Issue: 3 Pages: 741-749
  • DOI: 10.1042/bj20121201
  • Peer Reviewed
• [Presentation] プロテインホスファターゼPPM1Lの肥満形成への関与のメカニズムの解明 (2016)
  • Author(s): 小林孝安
  • Organizer: 第7回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 自然科学研究機構大会議室（愛知県岡崎市）
  • Year and Date: 2016-01-29
• [Presentation] Two post-translational modifications in mammalian B cnt/Cfdp1, a potential epigen etic factor: S250 phosphorylation and K268 acetylation in the conserved C-termin al region (2015)
  • Author(s): 岩下 新太郎, 中島 健太郎, 鈴木 健裕, 安田 武嗣, 坂本 泰一, 河野 俊之, 高橋 一朗, 小林 孝安, 大野 岩下 淑子, 今城 大海 忍, 堂前 直, 宋 時栄
  • Organizer: 第88回日本生化学会大会/第38回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] ノックアウトマウスを用いたプロテインホスファターゼPPM1Lの新規機能解明 (2015)
  • Author(s): 藤田 宏介, 篠田 康晴, 永浦 裕子, 草野 理恵, 渡邊 利雄, 松居 靖久, 阪上 洋行,佐藤達也, 舟橋淳一, 大西 素子, 田村 眞理, 小林 孝安,
  • Organizer: 日本生化学会東北支部会第81回例会
  • Place of Presentation: 東北大学片平さくらホール（宮城県仙台市）
  • Year and Date: 2015-05-09
• [Presentation] Targeted disruption of the mouse protein phosphatase PPM1L gene leads to structural abnormalities in the brain. (2014)
  • Author(s): Fujita,K., Shinoda, Y., Nagaura, Y., Kusano, R., Watanabe, T., Matsui, Y., Sakagami, H., Ohnishi, M., Tamura, S., Kobayashi, T.
  • Organizer: 11th International Conference on Protein Phosphatases.
  • Place of Presentation: Sendai
  • Year and Date: 2014-11-12 – 2014-11-14
• [Presentation] プ口テインホスファターゼPPM1Lの欠損は大脳皮質において軸索線維の異常を引き起こす (2014)
  • Author(s): 小林孝安, 藤田宏介, 篠田康晴, 永浦裕子, 草野理恵, 渡邊利雄, 松居靖久, 舟橋淳一, 佐藤達也, 阪上洋行, 大西素子, 田村眞理
  • Organizer: 第69回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] リン酸化クロマチン構成因子Bcnt/Cfdp1の多様性の分子基盤 (2014)
  • Author(s): 岩下新太郎, 鈴木健裕, 中島健太郎, 小林孝安, 安田武嗣, 大野-岩下淑子, 今城-大海忍, 宋時栄, 堂前直
  • Organizer: 第69回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] セリンスレオニンホスファターゼPP2C ε のゴルジ体局在タンパク質GCP60との機能連関 (2013)
  • Author(s): 篠田康晴, 福永浩司, 藤田宏介, 永浦裕子, 田村眞理,小林孝安
  • Organizer: 日本生化学会東北支部会第79回例会
  • Place of Presentation: 仙台
• [Presentation] PP2CαおよびPP2Cβの機能におけるN-ミリストイル化の役割 (2013)
  • Author(s): 小林孝安, 千田透子, 安藤正勝, 松木佑, 枡悠太郎, 永浦裕子,田村眞理
  • Organizer: 日本生化学会東北支部会第79回例会
  • Place of Presentation: 仙台
• [Presentation] N-ミリストイル化はPP2CαおよびPP2Cβの生理的基質の認識に必須である (2013)
  • Author(s): 小林孝安, 千田透子, 安藤正勝, 松木佑, 枡悠太郎, 永浦裕子,田村眞理
  • Organizer: 第86回日本生化学会年会
  • Place of Presentation: 横浜