Deciphering mechanism underlying neuro-vascular wiring by live-imaging using zebrafish

• Project Area: Vasculo-neural wiring and their interdependent crosstalk
• Project/Area Number: 22122003
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: MOCHIZUKI Naoki 独立行政法人国立循環器病研究センター, 研究所, 部長 (30311426)
• Co-Investigator(Kenkyū-buntansha): KOICHI Miura 国立循環器病研究センター, 研究所, 研究員 (20360349) ; HIROYUKI Nakajima 国立循環器病研究センター, 研究所, 研究員 (10467657) ; HAJIME Fukui 国立循環器病研究センター, 研究所, 研究員 (80551506) ; HARUKO Takano 国立循環器病研究センター, 研究所, 研究員 (40532891)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥118,040,000 (Direct Cost: ¥90,800,000、Indirect Cost: ¥27,240,000); Fiscal Year 2014: ¥21,710,000 (Direct Cost: ¥16,700,000、Indirect Cost: ¥5,010,000); Fiscal Year 2013: ¥22,750,000 (Direct Cost: ¥17,500,000、Indirect Cost: ¥5,250,000); Fiscal Year 2012: ¥24,830,000 (Direct Cost: ¥19,100,000、Indirect Cost: ¥5,730,000); Fiscal Year 2011: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2010: ¥23,010,000 (Direct Cost: ¥17,700,000、Indirect Cost: ¥5,310,000)
• Keywords: イメージング / 血管 / 神経 / 伴走 / ゼブラフィッシュ / 交感神経 / 脂肪 / ワイヤリング / VEGF

Outline of Final Research Achievements

Physiologocal homeostasis of human bodies is mainly regulated by the neural system and the vascular system delivering endocrine hormones. Both systems are consisted of circuits between central to periphery and vice versa. Therefore, neurons and blood vessels are found to exist side by side in certain anatomical regions.
We tried to search for neuro-vascular wiring system in vivo using zebrafish embryos and identified several regions where blood vessels and neurons exhibit parallel growth during embryogenesis. In addition, we demonstrate a mechanism how artery regulate the parallel growth of motor neurons.

Research Products

• [Journal Article] Recent advances in understanding of cardiovascular development by imaging of zebrafish. (2015)
  • Author(s): Fukuhara S, Fukui H, Wakayama Y, Ando K, Nakajima H, Mochizuki N.
  • Journal Title: Dev Growth Differ. Volume: 未定 Issue: 4 Pages: 109-122
  • DOI: 10.1111/dgd.12210
  • Peer Reviewed / Open Access
• [Journal Article] β-Catenin-dependent transcription is central to Bmp-mediated formation of venous vessels. (2015)
  • Author(s): Kashiwada T, Fukuhara S (Co-corresponding author), Terai K, Tanaka T, Wakayama Y, Ando K, Nakajima H, Fukui H, Yuge S, Saito Y, Gemma A, Mochizuki N.
  • Journal Title: Development Volume: 142 Pages: 497-509
  • DOI: 10.1242/dev.115576
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Visualizing the cell-cycle progression of endothelial cells in zebrafish. (2014)
  • Author(s): Fukuhara S (Co-corresponding author), Zhang J, Yuge S, Ando K, Wakayama Y, Sakaue-Sawano A, Miyawaki A, Mochizuki N.
  • Journal Title: Dev. Biol. Volume: 393 Issue: 1 Pages: 10-23
  • DOI: 10.1016/j.ydbio.2014.06.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The parallel growth of motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish. (2013)
  • Author(s): Kwon HB, Fukuhara S, Asakawa K, Ando K, Kashiwada T, Kawakami K, Hibi M, Kwon YG, Kim KW, Alitalo K, Mochizuki N.
  • Journal Title: Development Volume: 140 Pages: 4081-4090
  • Peer Reviewed
• [Journal Article] Rap1 potentiates endothelial cell junctions by spatially controlling myosin II activity and actin organization. (2013)
  • Author(s): Ando K, Fukuhara S, Moriya T, Obara Y, Nakahata N, Mochizuki N.
  • Journal Title: J Cell Biol. Volume: 202 Pages: 901-916
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 Guides Directional Angiogenesis Through Integrin αvβ5 Signaling for Recovery of Ischemic Retinopathy. (2013)
  • Author(s): Lee J, Kim KE, Choi DK, Jang JY, Jung JJ, Kiyonari H, Shioi G, Chang W, Suda T, Mochizuki N, Nakaoka Y, Komuro I, Yoo OJ, Koh GY
  • Journal Title: Sci Transl Med. Volume: 18
  • Peer Reviewed
• [Journal Article] Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase (2013)
  • Author(s): Miura, K.
  • Journal Title: Oncogene Volume: 32 Issue: 45 Pages: 5292-5301
  • DOI: 10.1038/onc.2012.571
  • Peer Reviewed
• [Journal Article] The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. (2012)
  • Author(s): Fukuhara S, Simmons S, Kawamura S, Inoue A,Tokudome T, Sunden Y, Arai Y, Moriwaki K, Ishida J, Uemura A, Kiyonari H, Abe T, Fukamizu A, Hirashima M, Sawa H, Aoki J, Ishii M, Mochizuki N
  • Journal Title: J. Clin. Invest. Volume: 122 Pages: 1416-1426
  • Peer Reviewed
• [Journal Article] EphrinA/EphA signal facilitates insulin-like growth factor-I-induced myogenie differentiation through suppression of the Ras/extracellular signal-regulated kinase 1/2 cascade in myoblast cell lines (2011)
  • Author(s): Minami M
  • Journal Title: Mol.Biol.Cell Volume: 22 Pages: 3508-3519
  • Peer Reviewed
• [Journal Article] Angiopoietin-1/Tie2 Signal Augments Basal Notch Signal Controlling Vascular Quiescence by Inducing Delta-Like 4 Expression through AKT-mediated Activation of {beta}-Catenin (2011)
  • Author(s): Zhang J
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 8055-8066
  • Peer Reviewed
• [Journal Article] Calpain protects the heart from hemodynamic stress (2011)
  • Author(s): Taneike M
  • Journal Title: J Biol.Chem. Volume: 286 Pages: 32170-32177
  • Peer Reviewed
• [Journal Article] Docking Protein Gab1 Is an Essential Component of Postnatal Angiogenesis After Ischemia via HGF/c-Met Signaling (2011)
  • Author(s): Shioyama W
  • Journal Title: Circ.Res. Volume: 108 Pages: 664-675
  • Peer Reviewed
• [Journal Article] AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. (2010)
  • Author(s): Nakano A
  • Journal Title: Nat.Cell Biol Volume: 12 Pages: 583-590
  • Peer Reviewed
• [Journal Article] Vascular Endothelial-Cadherin Stabilizes at Cell-Cell Junctions by Anchoring to Circumferential Actin Bundles through α- and β-Catenins in Cyclic AMP-Epac-Rap1 Signal-activated Endothelial Cells. (2010)
  • Author(s): Noda K
  • Journal Title: Mol.Biol.Cell Volume: 21 Pages: 584-596
  • Peer Reviewed
• [Journal Article] EphrinA1-EphA2 signal induces compaction and polarization of MDCK cells by inactivating ezrin through negative regulation of RhoA (2001)
  • Author(s): Wakayama Y
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 44243-44253
  • Peer Reviewed
• [Presentation] In vivo imaging of YAP dynamics in zebrafish vascular development (2014)
  • Author(s): Hiroyuki Nakajima, Sigetomo Fukuhara, Naoki Mochizuki
  • Organizer: The 18th International Vascular Biology Meeting （IVBM2014）
  • Place of Presentation: 京都メッセ
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] A small GTPase Rap1 potentiates vascular endothelial barrier function through actin rearrangement by spatially controlling the myosin II activity (2014)
  • Author(s): Koji Ando, Shigetomo Fukuhara, Takahiro Moriya, Naoki Mochizuki
  • Organizer: The 18th International Vascular Biology Meeting （IVBM2014）
  • Place of Presentation: 京都メッセ
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] イメージングによる心臓・血管発生メカニズムの解明 (2013)
  • Author(s): 望月直樹
  • Organizer: 第９０回日本生理学会大会
  • Place of Presentation: タワーホール船堀、東京
  • Year and Date: 2013-03-27
  • Invited
• [Presentation] in vivo imaging of signal transduction pathways involved in angiogenesis (2012)
  • Author(s): Shigetomo Fukuhara (Naoki Mochizuki)
  • Organizer: The 20th annual meeting of the Japanese vascular biology and medicine organization
  • Place of Presentation: Awagin hall, Tokushima
  • Year and Date: 2012-12-05
  • Invited
• [Presentation] Functions of Spns2 a sphingosine 1-phosphate transporter, in zebra fish and mammals (2011)
  • Author(s): 望月直樹
  • Organizer: The second pacific symposium on vascular Biology
  • Place of Presentation: Korea
  • Year and Date: 2011-11-01
• [Presentation] Imaging of cardiovasvular cells entering into cell cycle to dissect thesignaling n vascular quiescenceand cardiac regeneration (2011)
  • Author(s): 望月直樹
  • Organizer: The 8^<th> International Duodecim Symposium "Endothelial growth factors in cancer and cardiovascular diseases"
  • Place of Presentation: Finland
  • Year and Date: 2011-06-10
• [Presentation] Angiopoietin-1/Tie2-mediated vascular maturation and quiescence are reregulate by Dll4-Notch signaling (2010)
  • Author(s): Naoki Mochizuki
  • Organizer: Kloster Seeon Angiogenesis Meeting 2010
  • Place of Presentation: Kloster Seeon, Germany
• [Presentation] ゼブラフィッシュを用いた新たな心筋細胞増殖機構の解明
  • Author(s): 望月直樹
  • Organizer: 第３６回分子生物学会
  • Place of Presentation: 神戸国際会議場
  • Invited
• [Presentation] In vivo imaging技術の進歩
  • Author(s): Naoki Mochizuki
  • Organizer: 第５３回日本呼吸器学会
  • Place of Presentation: 東京国際フォーラム
  • Invited
• [Remarks] 国立循環器病研究センター研究所細胞生物学部、大阪大学医学系研究科連携大学院循環微小画像医学講座
  • URL: http://plaza.umin.ac.jp/ncvc/
• [Remarks] 独立行政法人国立循環器病研究センタ―研究所細胞生物学部
  • URL: http://plaza.umin.ac.jp/ncvc/
• [Remarks]
  • URL: http://plaza.umin.ac.jp/ncvc/
• [Patent(Industrial Property Rights)] 心筋細胞増殖誘導剤及びこれを含有する心筋梗塞治療用医薬組成物、並びに心筋細胞の製造方法 (2013)
  • Inventor(s): 望月直樹
  • Industrial Property Rights Holder: 独立行政法人 国立循環器病研究センター、他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-198591
  • Filing Date: 2013-09-25
• [Patent(Industrial Property Rights)] スフィンゴシン1-リン酸トランスポーターの新規機能 (2011)
  • Inventor(s): 望月直樹
  • Industrial Property Rights Holder: 国立循環器病研究センター
  • Industrial Property Number: 2011-198886
  • Filing Date: 2011-09-12