Sema3A-PTPdelta signaling regulates cortical dendritic growth

• Project/Area Number: 16K07062
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Women's Medical University (2017-2018); Yokohama City University (2016)
• Principal Investigator: Nakamura Fumio 東京女子医科大学, 医学部, 教授 (10262023)
• Research Collaborator: Jitsuki Aoi ; Shishikura Maria ; Kawashima Takeshi ; Okada Takako ; Goshima Yoshio
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: チロシンホスファターゼ / リン酸化 / PTPδ / Sema3A / Fyn / 樹状突起 / CRMP1 / チロシンリン酸化 / SIRPα / PTPRD / PTP delta / dendrite / SIRP alpha / シグナル伝達 / 神経科学

Outline of Final Research Achievements

Sema3A, an axon guidance molecule, repels peripheral sensory neurons. Sema3A also facilitates the growth of cortical pyramidal dendrites. We found that PTPdelta (PTPd), one of type IIa protein tyrosine phosphatases, mediates Sema3A-signaling. RNAi against PTPd attenuated Sema3A-induced growth cone collapse response of mouse embryonic sensory neurons. PTPd played a major role in Sema3A-dependent cortical dendritic growth. Ptpd-/-, Sema3a-/- and Ptpd+/-; Sema3a+/- mutant mice exhibited poor arborization of basal dendrites of cortical layer V neurons, indicating the genetic interaction of Sema3A and PTPd. In Ptpd-/- brains, Fyn and Src kinases were hyperphosphorylated at their C-terminal Tyr527 residues. Sema3A induced dephosphorylation of Tyr527 in the cortical dendrites of wild-type but of Ptpd-/-. Arborization of cortical basal dendrites was reduced in Fyn-/- and in Ptpd+/-; Fyn+/- mutants. PTPd mediates Sema3A-signaling through the activation of Fyn by dephosphorylation.

Academic Significance and Societal Importance of the Research Achievements

生後の中枢神経系では神経突起やシナプスが発達・成熟する。この異常が様々な神経疾患や高次機能障害の原因となる。入力側の神経突起である樹状突起は入力情報を統合する。その発達は神経機能に深く関わりを持つ。神経ガイド分子Sema3Aは大脳皮質・錐体細胞の樹状突起を発達させる。このSema3Aの作用を媒介する分子としてチロシンホスファターゼPTPδを同定した。さらにPTPδはチロシンキナーゼFynを介して樹状突起の発達を促進する。自閉症などの神経疾患の原因遺伝子として PTPδが同定されていることから、本研究の成果が神経疾患の新たな治療法や治療薬の開発に役立つと考えられる。

Research Products

• [Journal Article] Proteome and behavioral alterations in phosphorylation-deficient mutant Collapsin Response Mediator Protein2 knock-in mice. (2018)
  • Author(s): Nakamura H, Jitsuki-Takahashi A, Makihara H, Asano T, Kimura Y, Nakabayashi J, Yamashita N, Kawamoto Y, Nakamura F, Ohshima T, Hirano H, Tanaka F, Goshima Y
  • Journal Title: Neurochemistry international Volume: 119 Pages: 207-217
  • DOI: 10.1016/j.neuint.2018.04.009
  • Peer Reviewed
• [Journal Article] Label-free and spectral-analysis-free detection of neuropsychiatric disease biomarkers using an ion-sensitive GaInAsP nanolaser biosensor (2018)
  • Author(s): K. Watanabe, M. Nomoto, F. Nakamura, S. Hachuda, A. Sakata, T. Watanabe, Y. Goshima and T. Baba
  • Journal Title: Biosenors and Bioelectronics Volume: 117 Pages: 161-167
  • DOI: 10.1016/j.bios.2018.05.059
  • NAID: 120006643666
  • Peer Reviewed
• [Journal Article] A functional coupling between CRMP1 and Nav1.7 for retrograde propagation of Semaphorin3A signaling (2017)
  • Author(s): Yamane M, Yamashita N, Hida T, Kamiya Y, Nakamura F, Kolattukudy P, Goshima Y
  • Journal Title: Journal of Cell Science Volume: 130(8) Issue: 8 Pages: 1393-1403
  • DOI: 10.1242/jcs.199737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis (2017)
  • Author(s): Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao WN, Lalonde J, Nakamura H, Konopaske G, Sidor M, Pernia CD, Yamashita N, Wada M, Inoue Y, Nakamura F （15番目／５１名）他
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 22
  • DOI: 10.1073/pnas.1700111114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein Tyrosine Phosphatase δ Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase. (2017)
  • Author(s): Nakamura F, Okada T, Shishikura M, Uetani N, Taniguchi M, Yagi T, Iwakura Y, Ohshima T, Goshima Y, Strittmatter SM.
  • Journal Title: J Neurosci Volume: 37 Issue: 30 Pages: 7125-7139
  • DOI: 10.1523/jneurosci.2519-16.2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural basis for CRMP2-induced axonal microtubule formation (2017)
  • Author(s): Niwa Shinsuke、Nakamura Fumio、Tomabechi Yuri、Aoki Mari、Shigematsu Hideki、Matsumoto Takashi、Yamagata Atsushi、Fukai Shuya、Hirokawa Nobutaka、Goshima Yoshio、Shirouzu Mikako、Nitta Ryo
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 10681-10681
  • DOI: 10.1038/s41598-017-11031-4
  • NAID: 120006373796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor (2017)
  • Author(s): Masukawa Daiki、Koga Motokazu、Sezaki Anna、Nakao Yuka、Kamikubo Yuji、Hashimoto Tatsuo、Okuyama-Oki Yuki、Aladeokin Aderemi Caleb、Nakamura Fumio、Yokoyama Utako、Wakui Hiromichi、Ichinose Hiroshi、Sakurai Takashi、Umemura Satoshi、Tamura Koichi、Ishikawa Yoshihiro、Goshima Yoshio
  • Journal Title: JCI Insight Volume: 2 Issue: 18 Pages: 1-16
  • DOI: 10.1172/jci.insight.90903
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of receptor protein tyrosine phosphatase δ, PTPδ, in mouse central nervous system. (2016)
  • Author(s): Shishikura, M., Nakamura, F., Yamashita, N., Uetani, N., Iwakura, Y., and Goshima, Y.
  • Journal Title: Brain Res. Volume: 1642 Pages: 244-254
  • DOI: 10.1016/j.brainres.2016.03.030
  • Peer Reviewed / Open Access
• [Journal Article] Caerulein-induced pancreatitis augments the expression and phosphorylation of collapsin response mediator protein 4. (2016)
  • Author(s): Sato S, Nakamura F, Hiroshima Y, Nagashima Y, Kato I, Yamashita N, Goshima Y, Endo I
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: 23 Issue: 7 Pages: 422-431
  • DOI: 10.1002/jhbp.361
  • Peer Reviewed / Open Access
• [Journal Article] CRMP1 and CRMP2 have synergistic but distinct roles in dendritic development. (2016)
  • Author(s): Makihara H, Nakai S, Ohkubo W, Yamashita N, Nakamura F, Kiyonari H, Shioi G, Jitsuki-Takahashi A, Nakamura H, Tanaka F, Akase T, Kolattukudy P, Goshima Y.
  • Journal Title: Genes Cells Volume: 21 Issue: 9 Pages: 994-1005
  • DOI: 10.1111/gtc.12399
  • Peer Reviewed
• [Journal Article] Regulation of dendritic development by Semaphorin 3A through novel intracellular remote signaling (2016)
  • Author(s): Goshima Y, Yamashita N, Nakamura F, Sasaki Y
  • Journal Title: Cell Adh Migr Volume: 10 Issue: 6 Pages: 627-640
  • DOI: 10.1080/19336918.2016.1210758
  • Peer Reviewed / Open Access
• [Presentation] CRMP1 phosphorylation at tyrosine 504 participates in Sema3A- signaling (2018)
  • Author(s): Takeshi Kawashima, Yoshio Goshima, Fumio Nakamura.
  • Organizer: Cold Spring Harbor Meeting "MOLECULAR MECHANISMS OF NEURONAL CONNECTIVITY"
  • Int'l Joint Research
• [Presentation] Protein tyrosine phosphatase d mediates Semaphorin-3A-induced dendritic growth of cortical pyramidal neurons. (2018)
  • Author(s): Fumio Nakamura
  • Organizer: Workshop on Frontiers in Phosphatase Research and Drug Discovery (ICPP13)
  • Int'l Joint Research
• [Presentation] The involvement of Fyn phosphorylation of Collapsin Response Mediator Protein 1 (CRMP1) in Semaphorin 3A signaling (2017)
  • Author(s): Takeshi Kawashima, Fumio Nakamura, Yoshio Goshima1
  • Organizer: 日本神経科学学会大会
• [Presentation] FynによるCRMP1のチロシンリン酸化はSemaphorin3A情報伝達に関与する (2017)
  • Author(s): 河嶌 岳、中村 史雄、五嶋 良郎
  • Organizer: 第137回日本薬理学会関東部会
• [Presentation] FynによるCRMP1 Tyr504のリン酸化はSemaphorin 3A情報伝達に関与する (2017)
  • Author(s): 河嶌 岳、中村 史雄、五嶋 良郎
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Protein tyrosine phosphatase delta mediates Sema3A-induced cortical basal dendritic arborization through the activation of Fyn kinase. (2016)
  • Author(s): Nakamura F., Goshima Y., Strittmatter S.M.
  • Organizer: Axon Guidance, Synapse Formation & Regeneration
  • Place of Presentation: Cold Spring Harvbor Lab, NY, US
  • Year and Date: 2016-09-20
  • Int'l Joint Research
• [Presentation] Layer and region specific expression of receptor protein tyrosine phosphatase delta, PTPdelta, in mouse central nervous system. (2016)
  • Author(s): Shishikura M., Nakamura F. Goshima Y.
  • Organizer: 日本神経科学学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20