Molecular mechanisms of postnatal angiogenesis and neurogenesis

• Project/Area Number: 23249020
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: TAKAHASHI Masahide 名古屋大学, 医学(系)研究科(研究院), 教授 (40183446)
• Co-Investigator(Kenkyū-buntansha): ENOMOTO Atsushi 名古屋大学, 医学系研究科, 准教授 (20432255) ; ASAI Naoya 名古屋大学, 医学系研究科, 准教授 (80273233) ; MURAKUMO Yoshiki 北里大学, 医学部, 教授 (40324438)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥48,620,000 (Direct Cost: ¥37,400,000、Indirect Cost: ¥11,220,000); Fiscal Year 2013: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2012: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2011: ¥20,540,000 (Direct Cost: ¥15,800,000、Indirect Cost: ¥4,740,000)
• Keywords: Girdin / Akt / 細胞運動 / 神経新生 / 血管新生 / チロシンリン酸化 / focal adhesion / 遺伝子改変マウス / Daple / Disheveled / Rac / Wntシグナル

Research Abstract

To identify the cellular population responsible for the phenotype of girdin KO mice, newly generated girdin flox mice were crossed with nestin-promoter driven Cre-transgenic mice to obtain girdin conditional knockout mice.Our findings suggested that girdin expression in nestin cell lineage is responsible for the phenotype of girdin KO mice.
We used a mouse model of pathological ocular neovascularization: oxygen-induced retinopathy.Pathological neovascularization was decreased in S1416A knockin mice. The results demonstrate that girdin and its phosphorylation play an important role in neonatal vascular development and in pathological neovascularization in the retina.We also found that depletion of girdin attenuated venous smooth muscle cells migration and proliferation in vitro and intimal hyperplasia in vein grafts in vivo.
Moreover, we demonstrated that a girdin family protein, Dishevelled-associating protein Daple, controls the non-canonical Wnt/Rac pathway and cell motility

Research Products

• [Journal Article] The impact of Girdin expression on recurrence-free survival in patients with luminal-type breast cancer (2014)
  • Author(s): Nishimae K., Tsunoda, N., Yokoyama, Y., Kokuryo, T., Iwakoshi, A., Takahashi, M. and Nagiono, M.
  • Journal Title: Breast Cancer Volume: (in press)
  • Peer Reviewed
• [Journal Article] Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of siRNA for vein failure (2014)
  • Author(s): Miyachi, H., Mii, S., Enomoto, A., Murakumo, Y., Kato, T., Asai, N., Komori, K. and Takahashi, M.
  • Journal Title: J. Vasc. Surg. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of siRNA for vein failure (2014)
  • Author(s): Hiroki Miyachi, Shinji Mii, Atsushi Enomoto, Yoshiki Murakumo, Takuya Kato, Naoya Asai, Kimihiro Komori, Masahide Takahashi
  • Journal Title: Journal of Vascular Surgery Volume: 60 Issue: 2 Pages: 479-489
  • DOI: 10.1016/j.jvs.2013.06.080
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proteomic analysis of Girdin-interacting proteins in migrating new neurons in the postnatal mouse brain (2013)
  • Author(s): Ota, H., Hikita, T., Nishioka, T., Matsumoto, M., Ito, J., Asai, N., Enomoto, A., Takahashi, M., Kaibuchi, K., Sobue, K. and Sawamoto, K.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 442 Pages: 16-21
  • Peer Reviewed
• [Journal Article] Girdin and its phosphorylation dynamically regulate neonatal vascular development and pathological neovascularization in the retina (2013)
  • Author(s): Ito, T., Komeima, K., Yasuma, T., Enomoto, A., Asai, N., Iwase, S., Takahashi, M. and Terasaki, H.
  • Journal Title: Am. J. Pathol. Volume: 182 Pages: 586-596
  • Peer Reviewed
• [Journal Article] Girdin and its phosphorylation dynamically regulate neonatal vascular development and pathological neovascularization in the retina (2013)
  • Author(s): Takanori Ito, Keiichi Komeima, Tetsuhiro Yasuma, Atsushi Enomoto, Naoya Asai, Masato Asai, Sayoko Iwase, Masahide Takahashi, Hiroko Terasaki
  • Journal Title: American Journal of Pathology Volume: 182 Issue: 2 Pages: 586-596
  • DOI: 10.1016/j.ajpath.2012.10.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Proteomic analysis of Girdin-interacting proteins in migrating new neurons in the postnatal mouse brain (2013)
  • Author(s): Haruko Ota, Takao Hikita, Tomoki Nishioka, Mami Matsumoto, Jun Ito, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 442 Issue: 1-2 Pages: 16-21
  • DOI: 10.1016/j.bbrc.2013.10.126
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The impact of Girdin expression on recurrence-free survival in patients with luminal-type breast cancer (2013)
  • Author(s): Kazumi Nishimae, Nobuyuki Tsunoda, Yukihiro Yokoyama, Toshio Kokuryo, Akari Iwakoshi, Masahide Takahashi, Masato Nagino
  • Journal Title: Breast Cancer Volume: - Issue: 5 Pages: 445-451
  • DOI: 10.1007/s12282-013-0501-3
  • Peer Reviewed
• [Journal Article] Girdin locates in centrosome and midbody and plays an important role in cell division (2012)
  • Author(s): Mao, J.-Z., Jiang, P., Cui, S.-P., Ren, Y.-L., Zhao, J., Yin, X.-H., Enomoto, A., Liu, H.-J., Hou, L., Takahashi, M. and Zhang, B.
  • Journal Title: Cancer Sci. Volume: 103 Pages: 1780-1787
  • Peer Reviewed
• [Journal Article] Similar Phenotypes of Girdin germ-line and conditional knockout mice indicate a crucial role for Girdin in the nestin lineage (2012)
  • Author(s): Asai M., Asai, N., Murata, A., Yokota, H., Ohmori, K., Mii, S., Enomoto, A., Murakumo, Y. and Takahashi, M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 426 Pages: 533-538
  • Peer Reviewed
• [Journal Article] The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility (2012)
  • Author(s): Ishida-Takagishi, M., Enomoto, A., Asai, N., Ushida, K., Watanabe, T., Hashimoto, T., Kato, T., Weng, L., Matsumoto, S., Asai, M., Murakumo, Y., Kaibuchi, K., Kikuchi, A. and Takahashi, M.
  • Journal Title: Nature Commun. Volume: May 29 3 Pages: 859-859
  • Peer Reviewed
• [Journal Article] Involvement of Girdin in the determination of cell polarity during cell migration (2012)
  • Author(s): Ohara, K., Enomoto, A., Kato, T., Hashimoto, T., Isotani-Sakakibara, M., Asai, N., Ishida,-Takagishi, M., Weng, L., Nakayama, M., Watanabe, T., Kato, K., Kaibuchi, K., Murakumo, Y., Hirooka, Y., Goto, H. and Takahashi M.
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Girdin maintains the stemness of glioblastoma stem cells (2012)
  • Author(s): Natsume, A., Kato, T., Kinjo, S., Enomoto, A., Toda, H., Shimato, S., Ohka, F., Motomura, K., Kondo, Y., Miyata, T., Takahashi, M. and Wakabayashi, T.
  • Journal Title: Oncogene Volume: 31 Pages: 2715-2724
  • Peer Reviewed
• [Journal Article] Involvement of Girdin in the determination of cell polarity during cell migration (2012)
  • Author(s): Ohara K, Enomoto A, et al.
  • Journal Title: PLoS One Volume: 7 Issue: 5 Pages: e36681-e36681
  • DOI: 10.1371/journal.pone.0036681
  • Peer Reviewed
• [Journal Article] The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility (2012)
  • Author(s): Ishida-Takagishi M, Enomoto A, et al.
  • Journal Title: Nat Commun Volume: 3 Issue: 1 Pages: 859-859
  • DOI: 10.1038/ncomms1861
  • Peer Reviewed
• [Journal Article] Similar phenotypes of Girdin germ-line and conditional knockout mice indicate a crucial role for Girdin in the nestin lineage (2012)
  • Author(s): Masato Asai
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 426 Issue: 4 Pages: 533-538
  • DOI: 10.1016/j.bbrc.2012.08.122
  • Peer Reviewed
• [Journal Article] Girdin locates in centrosome and midbody and plays an important role in cell division (2012)
  • Author(s): Mao J-Z
  • Journal Title: Cancer Science Volume: 103 Issue: 10 Pages: 1780-1787
  • DOI: 10.1111/j.1349-7006.2012.02378.x
  • Peer Reviewed
• [Journal Article] Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice (2012)
  • Author(s): Nobutaka Ohgami
  • Journal Title: Neurobiol Aging Volume: 33 Issue: 3 Pages: 626.e25-626.e34
  • DOI: 10.1016/j.neurobiolaging.2011.04.002
  • Peer Reviewed
• [Journal Article] Girdin is an intrinsic regulator of neuroblast chain migration in the rostral migratory stream of the postnatal brain (2011)
  • Author(s): Wang, Y., Kaneko, N., Asai, N., Enomoto, A., Isotani-Sakakibara, M., Kato, T., Asai, M., Murakumo, Y., Ota, H., Hikita, T., Namba, T., Kuroda, K., Kaibuchi, K., Ming, G., Song, H., Sawamoto, K. and Takahashi, M.
  • Journal Title: J. Neurosci. Volume: 31 Pages: 8109-8122
  • Peer Reviewed
• [Journal Article] The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury (2011)
  • Author(s): Miyake, H., Maeda, K., Asai, N., Shibata, R., Ichimiya, H., Isotani-Sakakibara, M., Yamamura, Y., Kato, K., Enomoto, A., Takahashi, M. and Murohara, T.
  • Journal Title: Circ. Res. Volume: 108 Pages: 1170-1179
  • Peer Reviewed
• [Journal Article] The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury. (2011)
  • Author(s): Miyake H
  • Journal Title: Circulation Research Volume: 108 Issue: 10 Pages: 1170-1179
  • DOI: 10.1161/circresaha.110.236174
  • Peer Reviewed
• [Journal Article] Girdin is an intrinsic regulator of neuroblast chain migation in the Rostral migratory stream of the postnatal brain (2011)
  • Author(s): Yun Wang
  • Journal Title: Journal of Neuroscience Volume: 31 Pages: 8109-8122
  • Peer Reviewed
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis (2014)
  • Author(s): Takahashi, M., Enomoto, A. and Asai, N.
  • Organizer: International Symposium on Nanomedicine
  • Place of Presentation: Nagoya University Graduate School of Medicine, Nagoya
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis. (2014)
  • Author(s): Masahide Takahashi
  • Organizer: International Symposium on Nanomedicine
  • Place of Presentation: Nagoya University, Nagoya
  • Invited
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis (2013)
  • Author(s): Takahashi, M.
  • Organizer: Joint meeting of the Medical School of Nagoya University and the University of Adelaide
  • Place of Presentation: The University of Adelaide, Adelaide, Australia
  • Year and Date: 2013-05-27
• [Presentation] Roles of the Akt substrate Girdin in tumor progression, angiogenesis and neurogenesis (2013)
  • Author(s): Takahashi, M.
  • Organizer: Joint meeting of the Medical School of Nagoya University and the Medical University of Vienna
  • Place of Presentation: Center for Brain Research, Medical University of Vienna, Vienna, Austria
  • Year and Date: 2013-01-28
• [Presentation] Roles of the Akt substrate Girdin in cell motility (2013)
  • Author(s): Takahashi, M.
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo
• [Presentation] Roles of the Akt substrate Girdin in cell motility (2013)
  • Author(s): Masahide Takahashi
  • Organizer: 1st International symposium on protein modifications in pathogenic dysregulation of signaling
  • Place of Presentation: The Institute of Medical Science, The University of Tokyo (Tokyo)
  • Invited
• [Presentation] アクチン結合蛋白Girdinおよびそのファミリー分子による細胞運動制御機構 (2012)
  • Author(s): 高橋雅英
  • Organizer: 第3次対がん10か年総合戦略・文部科学省がん支援活動:合同公開シンポジウム
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2012-01-30
• [Presentation] Roles of the Akt substrate Girdin in cancer progression, angiogenesis and Neurogenesis (2012)
  • Author(s): Takahashi, M.
  • Organizer: Global Center of Excellence (COE) Program, The 4th International Symposium: Global COE symposium on Neuro-Tumor Biology and Medicine
  • Place of Presentation: Westin Nagoya Castle, Nagoya
• [Presentation] Role of the Akt substrate Girdin in cancer progression and angiogenesis (2012)
  • Author(s): Masahide Takahashi
  • Organizer: BIT's 5th annual world cancer congress-2012
  • Place of Presentation: Beijing, China
  • Invited
• [Presentation] Aktの基質蛋白Girdinのがんの進展、血管新生における役割 (2012)
  • Author(s): 高橋雅英
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌）
  • Invited
• [Presentation] Roles of the Akt substrate Girdin in cancer progression, angiogenesis and neurogenesis (2012)
  • Author(s): Masahide Takahashi
  • Organizer: The 4th international symposium: Global COE symposium on neuro-tumor biology and medicine
  • Place of Presentation: Westin Nagoya Castle (Nagoya)
  • Invited
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis (2011)
  • Author(s): Masahide Takahashi
  • Organizer: Global Center of Excellence (COE) Program, The 3rd International Symposium
  • Place of Presentation: 名古屋(招待講演)
  • Year and Date: 2011-12-08
• [Presentation] Aktキナーゼ基質蛋白Girdinの細胞運動における役割 (2011)
  • Author(s): 高橋雅英
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋(招待講演)
  • Year and Date: 2011-10-05
• [Presentation] Aktシグナルと細胞運動 (2011)
  • Author(s): 高橋雅英
  • Organizer: 第4回神戸がん研究会
  • Place of Presentation: 神戸(招待講演)
  • Year and Date: 2011-06-24
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis (2011)
  • Author(s): Takahashi, M.
  • Organizer: Global Center of Excellence (COE) Program, The 3rd International Symposium: New trends in basic and clinical cancer research for innovative Therapy
  • Place of Presentation: Midland Hall, Nagoya
• [Presentation] Roles of the Akt substrate Girdin in cancer progression and angiogenesis
  • Author(s): Masahide Takahashi
  • Organizer: Joint meeting of the Medical School of Nagoya University and the University of Adelaide
  • Place of Presentation: Adelaide, Australia
  • Invited
• [Presentation] Roles of the Akt substrate Girdin in tumor progression, angiogenesis and neurogenesis
  • Author(s): Masahide Takahashi
  • Organizer: Joint meeting of the medical school of Nagoya and the medical university of Vienna
  • Place of Presentation: Vienna, Austria
  • Invited
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/patho2/