HOME > Members > GCOE Organizing Members > Masahide Takahashi MD, PhD


Masahide Takahashi MD, PhDProfessor, Department of Tumor Pathology, Nagoya University Graduate School of Medicine


Specialized field

Experimental pathology
Mechanisms of carcinogenesis and organogenesis by oncogenes and cancer-related genes

Career Summary

1983-1985
Research Fellow, (Dana-Farber Cancer Institute, Harvard Medical School)
1985-1990
Research Fellow, (Division of Oncological Pathology, Aichi Cancer Center Research Institute)
1990-1991
Research Associate (Department of Pathology, Nagoya University School of Medicine)
1990-1995
Assistant Professor (Department of Pathology, Nagoya University School of Medicine)
1995-1996
Associate Professor (Department of Pathology, Nagoya University School of Medicine)
1996-2000
Professor (Department of Pathology, Nagoya University School of Medicine)
2000-
Professor (Department of Pathology, Nagoya University Graduate School

Research Theme

Roles of cancer-related genes in oncogenesis and organogenesis

Research Summary

Aim: Cell migration that is initiated in response to multiple extracellular cues such as growth factors and cell-extracellular matrix adhesions requires dynamic and spatially regulated changes of the actin cytoskeleton, microtubules, adhesion molecules, and extracellular matrix. In multicellular organisms, cell migration is highly integrated process that orchestrates embryonic morphogenesis, contributes to tissue repair and regeneration, and drives disease progression in cancer, atherosclerosis, and immune diseases. We identified an Akt substrate, designated Girdin, which is an actin binding protein and have been studying its role in cell migration. Using the generated Girdin-deficient mice, we further investigated the function of Girdin in neurogenesis.

Results: Girdin-deficient mice died by postnatal day 25, although we did not observe any serious pathological changes such as hemorrhage, edema or inflammation. Thus, the cause of their death is unknown. Histological analyses of Girdin-deficient mice revealed the abnormalities in the dentate gyrus (DG) and olfactory bulb. The DG is a unique brain region in that most of its neurons are formed postnatally, and neurogenesis persists throughout life. We first examined cells expressing doublecortin (Dcx), a microtubule-associated protein required for neuronal migration that is employed as a marker of immature neurons. In Girdin-deficient mice, Dcx-positive immature dentate granule cells (DGC) were dispersed through all layers of the granule cell layer (GCL) of the DG whereas they were consistently found in the inner third of the GCL or the subgranular zone (SGZ) in wild-type mice (Figure). In addition, retroviral constructs were engineered to coexpress Zoanthus green fluorescent protein ZsGreen and short hairpin RNA (shRNA) to knock down the expression of endogenous Girdin. The engineered retroviruses were stereostactically injected into the hilar region of P5 rat hippocampi to infect only dividing progenitors in vivo. At 2 weeks postinjection, the majority of Girdin shRNA/ZsGreen-expressing neurons had migrated over long distances to the outer third of the GCL and the molecular layer (ML). In contrast, control shRNA/ZsGreen-expressing neurons primarily settled in the inner two-thirds of the GCL. These findings indicate that Girdin regulates the positioning of immature DGCs. Regarding the olfactory bulb, we observed the migration delay of Dcx-positive immature neurons in rostral migratory stream (RMS) which were generated from the subventricular zone.

Based on the Girdin expression profile and evidence that the expression of DISC1 (Disrupted-In-Schizophrenia 1, a susceptibility gene for major psychiatric disorders) is most prominent in the developing DG and hippocampus, we speculated that DISC1 cooperates with Girdin in these regions. The interaction between exogenously expressed DISC1 and Girdin was shown in immunoprecipitation. In addition, endogenous DISC1 was detected in Girdin immunoprecipitates from rat embryonic brain, suggesting that Girdin is a physiologically relevant partner of DISC1.

In cultured rat embryonic hipocampal neurons, Girdin expression was detected in neuronal cell bodies and on all processes within a day after plating. After 2 days in vitro, Girdin localized along the Tau-1 positive axons and accumulated at the expanded tips of the processes. ShRNA- mediated knockdown of Girdin led to a decrease of its immunoreactivity in neuritis, impairing the development and elongation of axons without affecting neuronal polarity. Girdin knockdown inhibited the total number of neurites, suggesting that Girdin is involved in the formation/maturation of both axons and dendrites. Consistent with these findings, the development and lamination of mossy fibers, axons of DGCs that are the main excitatory input from the DG to the hippocampus, were severely impaired in Girdin-deficient mice. Impaired pathfinding of mossy fibers seems to result in aberrant innervations of DGCs and CA3 pyramidal cells in Girdin-deficient mice, although this will need to be further investigated by electrophysiological experiments to draw a conclusion. It will be also necessary to generate Girdin-conditional knockout mice and identify binding partners to elucidate the precise roles of Girdin in neurogenesis.

Principal Research Achievement

  1. Natsume A, Kato T, Kinjo S, Enomoto A, Toda H, Shimato S, Ohka F, Motomura K, Kondo Y, Miyata T, Takahashi M, Wakabayashi T: Girdin maintains the stemness of glioblastoma stem cells. Oncogene, in press (2012)
  2. Kee HJ, Kim JR, Joung H, Choe N, Lee SE, Eom GH, Kim JC, Geyer SH, Jijiwa M, Kato T, Kawai K, Weninger WJ, Seo SB, Nam KI, Jeong MH, Takahashi M, Kook H: Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb1. Cell Death Differ, 19, 121-131 (2012)
  3. Ohgami N, Ida-Eto M, Sakashita N, Sone M, Nakashima T, Tabuchi K, Hoshino T, Shimada A, Tsuzuki T, Yamamoto M, Sobue G, Jijiwa M, Asai N, Hara A, Takahashi M, Kato M: Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice. Neurobiol Aging, 33, 626 e625-634 (2012)
  4. Asano E, Maeda M, Hasegawa H, Ito S, Hyodo T, Yuan H, Takahashi M, Hamaguchi M, Senga T: Role of palladin phosphorylation by extracellular signal-regulated kinase in cell migration. PLoS One, 6, e29338 (2011)
  5. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K: Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet, 20, 4666-4683 (2011)
  6. Motegi Y, Katayama K, Sakurai F, Kato T, Yamaguchi T, Matsui H, Takahashi M, Kawabata K, Mizuguchi H: An effective gene-knockdown using multiple shRNA-expressing adenovirus vectors. J Control Release, 153, 149-153 (2011)
  7. 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 GL, Song H, Sawamoto K, Takahashi M: Girdin is an intrinsic regulator of neuroblast chain migration in the rostral migratory stream of the postnatal brain. J Neurosci, 31, 8109-8122 (2011)
  8. Miyake H, Maeda K, Asai N, Shibata R, Ichimiya H, Isotani-Sakakibara M, Yamamura Y, Kato K, Enomoto A, Takahashi M, Murohara, T: The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury. Circ Res, 108, 1170-1179 (2011)
  9. Saito S, Murakumo Y, Tsuzuki T, Dambara A, Kato T, Enomoto A, Asai N, Maruyama S, Matsuo S, Takahashi M: Analysis of GDNF-inducible zinc finger protein 1 expression in human diseased kidney. Human Pathol, 42, 848-858 (2011)
  10. Matsushita E, Asai N, Enomoto A, Kawamoto Y, Kato T, Mii S., Maeda K, Shibata R, Hattori S, Hagikura M, Takahashi K, Sokabe M, Murakumo Y, Murohara T, Takahashi M: Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cell. Mol Biol Cell, 22, 736-747 (2011)
  11. Miyamoto R, Jijiwa M, Asai M, Kawai K, Ishida-Takagishi M, Mii S, Asai N, Enomoto A, Murakumo Y, Yoshimura A, Takahashi, M: Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice. Dev Biol, 349, 160-168 (2011)
  12. Hagikura M, Murakumo Y, Hasegawa M, Jijiwa M, Hagiwara S, Mii S, Hagikura S, Matsukawa Y, Yoshino Y, Hattori R, Wakai K, Nakamura S, Gotoh M, Takahashi M: Correlation of pathological grade and tumor stage of urothelial carcinoma with CD109 expression. Pathol Int, 60, 735-743 (2010)
  13. Ohgami N, Ida-Eto M, Shimotake T, Sakashita N, Sone M, Nakashima T, Tabuchi K, Hoshino T, Shimada A, Tsuzuki T, Yamamoto M, Sobue G, Jijiwa M, Asai N, Hara A, Takahashi, M, Kato M: c-Ret-mediated hearing loss in mice with Hirschsprung disease. Proc Natl Acad Sci USA, 107, 13051-13056 (2010)
  14. Yamaguchi M, Suyari O, Nagai R, Takahashi M: dGirdin a new player of Akt /PKB signaling in Drosophila Melanogaster. Front Biosci, 15, 1164-1171 (2010)
  15. Weng L, Enomoto A, Ishida-Takagishi M, Asai N, Takahashi M: Girding for migratory cues: Role of the Akt substrate Girdin in cancer progression and angiogenesis. Cancer Sci, 101, 836-842 (2010)
  16. Kurotsuchi A, Murakumo Y, Jijiwa M, Kurokawa K, Itoh Y, Kodama Y, Kato T, Enomoto A, Asai N, Terasaki H, Takahashi M: Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cells. Cancer Sci, 101, 1147-1155 (2010)
  17. Kato M, Takeda K, Hossain K, Thang ND, Kaneko Y, Kumasaka M, Yamanoshita O, Uemura N, Takahashi M, Ohgami N, Kawamoto Y: A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation. J Cell Biochem, 110, 399-407 (2010)
  18. Hagiwara S, Murakumo Y, Mii S, Shigetomi T, Yamamoto N, Furue H, Ueda M, Takahashi M: Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene, 29, 2181-2191 (2010)
  19. Ohshima Y, Yajima I, Kumasaka MY, Yanagishita T, Watanabe D, Takahashi M, Inoue Y, Ihn H, Matsumoto Y, Kato M: CD109 expression levels in malignant melanoma. J Dermatol Sci, 57, 140-142 (2010)
  20. Kumasaka MY, Yajima I, Hossain K, Iida M, Tsuzuki T, Ohno T, Takahashi M, Yanagisawa M, Kato M: A novel mouse model for de novo Melanoma. Cancer Res, 70, 24-29 (2010)
  21. Hagiwara S et al., Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene, in press (2010)
  22. Lu B, Cebrian C, Chi X, Kuure S, Kuo R, Bates CM, Arber S, Hassell J, MacNeil L, Hoshi M, Jain S, Asai N, Takahashi M, Schmidt-Ott K, Barasch J, D’Agati V. Costantini F. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature Genet, 41, 1295-1302 (2009)
  23. Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakumo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of Disrupted-in-Schizophrenia 1-interacting protein Girdin in postnatal development of the dentate gyrus. Neuron, 63, 774-787 (2009)
  24. Puseenam A, Yoshioka Y, Nagai R, Hashimoto R, Suyari O, Itoh M, Enomoto A, Takahashi M, Yamaguchi M. A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size. Exp Cell Res, 315, 3370-3380 (2009)
  25. Jiang P, Enomoto A, Takahashi M. Cell biology of the movement of breast cancer cells: intracellular signaling and the actin cytoskeleton. Cancer Lett, 284, 122-130 (2009)
  26. Chi X, Michos O, Shakya R, Riccio P, Enomoto H, Licht JD, Asai N, Takahashi M, Ohgami N, Kato M, Mendelsohn C, Costantini, F. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell, 17, 199-209 (2009)
  27. Kato T, Shimono Y, Hasegawa M, Jijiwa M, Enomoto A, Asai N, Murakumo Y, Takahashi M. Characterization of the HDAC1 complex that regulates the sensitivity of cancer cells to oxidative stress. Cancer Res, 69, 3597-3604 (2009)
  28. Hasegawa T, Enomoto A, Kato T, Kawai K, Miyamoto R, Jijiwa M, Ichiahara M, Ishida M, Asai N, Murakumo Y, Ohara K, Niwa Y, Goto H, Takahashi M. Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice. Oncogene, 27, 5684-5695 (2008)
  29. Jijiwa M, Kawai K, Fukihara J, Nakamura A, Hasegawa M, Suzuki C, Sato T, Enomoto A, Asai N, Murakumo Y, Takahashi M. GDNF-mediated Signaling via RET Tyrosine 1062 is Essential for Maintenance of Spermatogonial Stem Cells. Genes Cells, 13, 365-374 (2008)
  30. Kitamura T et al. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nature Cell Biol. 10: 329-337 (2008)
  31. Jiang P et al. An actin-binding protein Girdin regulates the motility of breast cancer cells. Cancer Res. 68: 1310-1318 (2008)
  32. Asai N et al. Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. Development 133: 4507-4516 (2006)
  33. Uchida M et al. Dok-4 regulates GDNF-dependent neurite outgrowth through downstream activation of Rap1 and mitogen-activated protein kinase. J. Cell Sci. 119: 3067-3077 (2006)
  34. Enomoto A et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell 9: 389-402 (2005)
  35. Morinaga T et al. GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region. Nucleic Acids Res. 33: 4191-4201 (2005)
  36. Jijiwa M et al. A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia. Mol. Cell. Biol. 24: 8026-8036 (2004)
  37. Hashimoto M et al. Expression of CD109 in human cancer. Oncogene 23: 3716-3720 (2004)
  38. Fukuda T et al. Novel mechanism of regulation of Rac activity and lamellipodia formation by RET tyrosine kinase. J. Biol. Chem. 277: 19114-19121 (2002)
  39. Iwashita T et al. Functional analysis of RET with Hirschsprung’s mutations affecting its kinase domain. Gastroenterology 121: 24-33 (2001)
  40. Takahashi M et al. The GDNF/RET signaling pathway and human diseases. Cysokine & Growth Factor Reviews 12: 361-373 (2001)
  41. Kawai K et al. Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation. Cancer Res. 60: 5254-5260 (2000)
  42. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary carcinoma, and Hirschsprung’s disease phenotype. Cancer Res. 57: 2870-2872 (1997)
  43. Klein RD et al. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387: 717-721 (1997)
  44. Treanor JJS et al. Characterization of a multicomponent receptor for GDNF. Nature 382: 80-83 (1996)
  45. Asai N et al. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol. Cell. Biol. 15: 1613-1619 (1995)
  46. Iwamoto T et al. Aberrant melanogenesis and melanocytic tumor development in transgenic mice that carry a metallothionein/ret fusion gene. EMBO J. 10: 3167-3175 (1991)
  47. Takahashi M et al. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42: 581-588 (1985)

Award

Incitement Award of the Japanese Cancer Association (1990 ,The Japanese Cancer Association )
JSP Yong Investigator Award (1993, The Japanese Society of Pathology)
Japan Pathology Award (2001 ,The Japanese Society of Pathology)
Yomiuri-Tokai Medical Award (2006, The Yomiuri Shimbun)

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