Research activity information

• A Gfrα3 Conditional Knockout Mouse Reveals a Requirement for GFRα3 / RET Signaling in Cholecystokinin‐Positive Enteroendocrine Cells

  Susan Simanjaya, Masato Kinoshita, Mukhamad Sunardi, Keisuke Ito, Masakazu Shinohara, Takaya Abe, Yuzo Kodama, Toshihiro Uesaka, Hideki Enomoto

  ABSTRACT The receptor tyrosine kinase RET regulates the development of multiple neuronal populations through GFRα co‐receptors and their cognate ligands. Recent work has shown that RET is also required for enteroendocrine cell (EEC) function; however, the specific GFRα receptor operating in EECs has remained unclear. Here, we identify GFRα3 as the predominant GFRα receptor expressed in EECs. To determine its cell‐autonomous role, we generated a Gfrα3 conditional allele and inactivated the Gfrα3 gene specifically in the intestinal epithelium. These Gfrα3 IEcKO mice exhibited a selective reduction in the number of CCK ⁺ EECs among multiple EEC subtypes. A comparative decrease in CCK ⁺ EECs in Ret IEcKO mice suggests that RET/GFRα3 signaling is required for the development and/or maintenance of this EEC lineage. Although CCK ⁺ EECs can indirectly influence glucose metabolism, Gfrα3 IEcKO mice showed no significant change in glucose tolerance under high‐fat diet (HFD) conditions. In contrast, they exhibited modest lipid malabsorption on HFD. Together, these findings demonstrate that GFRα3 is implicated in the structure and function of CCK EECs and highlight the utility of the Gfrα3 conditional allele for dissecting the biology of GFRα3‐expressing cells.

  Wiley, Feb. 2026, genesis, 64(1) (1)

  Scientific journal


• Intramuscular enteric glia persist in Hirschsprung disease and undergo neurogenesis in response to GDNF-NCAM1 signaling

  Jessica L. Mueller, Chris Han, Abigail Leavitt, Vipin Chauhan, Leah Ott, Richard A. Guyer, Toshihiro Uesaka, Hideki Enomoto, Lily Cheng, Ryo Hotta, Alan J. Burns, Rhian Stavely, Allan M. Goldstein

  Sep. 2025, SCIENTIFIC REPORTS, 15(1) (1), English

  [Refereed]

  Scientific journal


• The long-term survival of enteroendocrine cells depends on their subtype and is linked to peripheral sensory innervation

  Salsabila Luthfi Sesotyosari, Masato Kinoshita, Mukhamad Sunardi, Mo Lihan, Akimasa Orii, Takaya Abe, Hiroshi Kiyonari, Tatsuya Nakai, Toshihiro Uesaka, Yuzo Kodama, Hideki Enomoto

  Corresponding, May 2025, DEVELOPMENT GROWTH & DIFFERENTIATION, 67(4) (4), 205 - 214, English

  [Refereed]

  Scientific journal


• Pcgf1 gene disruption reveals primary involvement of epigenetic mechanism in neuronal subtype specification in the enteric nervous system

  Bayu Pratama Putra, Keisuke Ito, Carla Cirillo, Mukhamad Sunardi, Haruhiko Koseki, Toshihiro Uesaka, Hideki Enomoto

  Oct. 2023, DEVELOPMENT GROWTH & DIFFERENTIATION, 65(8) (8), 461 - 469, English, Domestic magazine

  [Refereed]

  Scientific journal


• A Single RET Mutation in Hirschsprung Disease Induces Intestinal Aganglionosis Via a Dominant-Negative Mechanism

  Mukhamad Sunardi, Keisuke Ito, Yuya Sato, Toshihiro Uesaka, Mitsuhiro Iwasaki, Hideki Enomoto

  2023, CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 15(6) (6), 1505 - 1524, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Uts2b is a microbiota-regulated gene expressed in vagal afferent neurons connected to enteroendocrine cells producing cholecystokinin

  Yuta Yoshioka, Yoshihisa Tachibana, Toshihiro Uesaka, Hiroyuki Hioki, Yuya Sato, Takumi Fukumoto, Hideki Enomoto

  Jun. 2022, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 608, 66 - 72, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Enhanced enteric neurogenesis by Schwann cell precursors in mouse models of Hirschsprung disease

  Toshihiro Uesaka, Mitsumasa Okamoto, Mayumi Nagashimada, Yoshihiro Tsuda, Miho Kihara, Hiroshi Kiyonari, Hideki Enomoto

  Lead, Nov. 2021, GLIA, 69(11) (11), 2575 - 2590, English, International magazine

  [Refereed]

  Scientific journal


• Increased RET Activity Coupled with a Reduction in the RET Gene Dosage Causes Intestinal Aganglionosis in Mice

  Mitsumasa Okamoto, Toshihiro Uesaka, Keisuke Ito, Hideki Enomoto

  May 2021, ENEURO, 8(3) (3), ENEURO.0534 - 20.2021, English

  [Refereed]

  Scientific journal


• Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B-and Hirschsprung disease-associated missense mutations of the RET gene

  Taichi Nakatani, Mitsuhiro Iwasaki, Atsuhiro Yamamichi, Yuta Yoshioka, Toshihiro Uesaka, Yuko Bitoh, Kosaku Maeda, Takumi Fukumoto, Tatsuya Takemoto, Hideki Enomoto

  May 2020, DEVELOPMENT GROWTH & DIFFERENTIATION, 62(4) (4), 214 - 222, English, Domestic magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system

  Mitsumasa Okamoto, Yuta Yoshioka, Kosaku Maeda, Yuko Bito, Takumi Fukumoto, Toshihiro Uesaka, Hideki Enomoto

  May 2019, GENESIS, 57(5) (5), e23292, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Development of the intrinsic and extrinsic innervation of the gut.

  Toshihiro Uesaka, Heather M Young, Vassilis Pachnis, Hideki Enomoto

  Sep. 2016, Developmental biology, 417(2) (2), 158 - 67, English, International magazine

  [Refereed]

  Scientific journal


• Neuronal Differentiation in Schwann Cell Lineage Underlies Postnatal Neurogenesis in the Enteric Nervous System

  Toshihiro Uesaka, Mayumi Nagashimada, Hideki Enomoto

  Lead, Jul. 2015, JOURNAL OF NEUROSCIENCE, 35(27) (27), 9879 - 9888, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• GDNF Signaling Levels Control Migration and Neuronal Differentiation of Enteric Ganglion Precursors

  Toshihiro Uesaka, Mayumi Nagashimada, Hideki Enomoto

  Lead, Oct. 2013, JOURNAL OF NEUROSCIENCE, 33(41) (41), 16372 - 16382, English

  [Refereed]

  Scientific journal


• Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system

  Chihiro Nishiyama, Toshihiro Uesaka, Takayuki Manabe, Yohei Yonekura, Takashi Nagasawa, Donald F. Newgreen, Heather M. Young, Hideki Enomoto

  Sep. 2012, NATURE NEUROSCIENCE, 15(9) (9), 1211 - U64, English

  [Refereed]

  Scientific journal


• Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression

  Mayumi Nagashimada, Hiroshi Ohta, Chong Li, Kazuki Nakao, Toshihiro Uesaka, Jean-Francois Brunet, Jeanne Amiel, Delphine Trochet, Teruhiko Wakayama, Hideki Enomoto

  Sep. 2012, JOURNAL OF CLINICAL INVESTIGATION, 122(9) (9), 3145 - 3158, English

  [Refereed]

  Scientific journal


• Neural Precursor Death Is Central to the Pathogenesis of Intestinal Aganglionosis in Ret Hypomorphic Mice

  Toshihiro Uesaka, Hideki Enomoto

  Lead, Apr. 2010, JOURNAL OF NEUROSCIENCE, 30(15) (15), 5211 - 5218, English

  [Refereed]

  Scientific journal


• Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice

  Toshihiro Uesaka, Mayumi Nagashimada, Shigenobu Yonemura, Hideki Enomoto

  Lead, May 2008, JOURNAL OF CLINICAL INVESTIGATION, 118(5) (5), 1890 - 1898, English

  [Refereed]

  Scientific journal


• Conditional ablation of GFRα1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype

  Toshihiro Uesaka, Sanjay Jain, Shigenobu Yonemura, Yasuo Uchiyama, Jeffrey Milbrandt, Hideki Enomoto

  Lead, Jun. 2007, DEVELOPMENT, 134(11) (11), 2171 - 2181, English

  [Refereed]

  Scientific journal


• Differential gene expression and functional analysis implicate novel mechanisms in enteric nervous system precursor migration and neuritogenesis

  Bhupinder P. S. Vohra, Keiji Tsuji, Mayumi Nagashimada, Toshihiro Uesaka, Daniel Wind, Ming Fu, Jennifer Armon, Hideki Enomoto, Robert O. Heuckeroth

  Oct. 2006, DEVELOPMENTAL BIOLOGY, 298(1) (1), 259 - 271, English

  [Refereed]

  Scientific journal


• Tumor induction by azoxymethane (AOM) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in F344 rat gastric mucosa featuring intestinal metaplasia caused by X-irradiation.

  S Kashiwabara, N Kashimoto, T Uesaka, K Wakabayashi, K Kamiya, H Watanabe

  Male F344 5-week-old rats were X-irradiated, and 16 weeks after the first dose, azoxymethane (AOM) was injected or 2-amino-1 -methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) was given by intragastric intubation. Tumors in the pylorus of the glandular stomach were observed in 4 out of the 29 animals receiving X-rays + AOM and in 4 out of the 25 animals receiving X-rays + PhIP, 12 months after administration. No such lesions were found in the chemical or X-ray alone groups. Intestinal metaplasia and some induced tumors were positive for CDX2. It was concluded that the presence of intestinal metaplasia may increase sensitivity to the induction of gastric tumors by colon carcinogens.

  Jun. 2005, Journal of experimental & clinical cancer research : CR, 24(2) (2), 305 - 12, English, International magazine

  Scientific journal


• Identifying target genes regulated downstream of Cdx2 by microarray analysis.

  Toshihiro Uesaka, Noriko Kageyama, Hiromitsu Watanabe

  Mar. 2004, Journal of molecular biology, 337(3) (3), 647 - 60, English, International magazine

  [Refereed]

  Scientific journal


• Acquisition of a gastric or duodenal phenotype on heterotropic transplantation of esophagus and bladder tissues in F344 rats.

  H Watanabe, K Kinoshita, M Katayama, K Kin, Y Kominami, R Gon, M Nishiki, A Sasaki, M Shiraishi, T Uesaka, O Katoh

  Cell differentiation is very important but not well understood. In the present study the ability of various tissues to newly-differentiate when transplanted into the fundus or the duodenum in rats was tested. Pieces of esophagus, bladder, diaphragm and trachea from 8-week-old male F344 rats were transplanted into the gastric fundus or duodenum of females and examined after 3 or 6 months. While the diaphragm was not recognizable as a muscle layer in either the stomach or the duodenum, the esophagus and trachea persisted, the latter with the presence of cartilage. Esophagus grafts transplanted into the glandular stomach and duodenum, newly-differentiated into gastric and duodenal mucosa, respectively. Goblet cells with alcian-blue positive mucin appeared in bladder tissue implanted into the duodenum. Six months after the operation, their numbers had increased and cytoplasm alkaline phosphatase (ALP) positivity was noted. Gastrointestinal and also bladder stem cells may thus have multipotential ability for differentiation and may be able to newly-differentiate when transplanted into different environments in the gastrointestinal tract.

  Dec. 2003, Journal of experimental & clinical cancer research : CR, 22(4) (4), 619 - 22, English, International magazine

  Scientific journal


• A water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia suppresses azoxymethane-induction of colon cancers in male F344 rats.

  Huimei Lu, Eikai Kyo, Toshihiro Uesaka, Osamu Katoh, Hiromitsu Watanabe

  Mar. 2003, Oncology reports, 10(2) (2), 375 - 9, English, International magazine

  [Refereed]

  Scientific journal


• Heparin-binding EGF-like growth factor gene transcription regulated by Cdx2 in the intestinal epithelium.

  Toshihiro Uesaka, Huimei Lu, Osamu Katoh, Hiromitsu Watanabe

  Oct. 2002, American journal of physiology. Gastrointestinal and liver physiology, 283(4) (4), G840-7 - G847, English, International magazine

  [Refereed]

  Scientific journal


• Prevention of development of N,N'-dimethylhydrazine-induced colon tumors by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male ICR mice.

  Huimei Lu, Eikai Kyo, Toshihiro Uesaka, Osamu Katoh, Hiromitsu Watanabe

  Feb. 2002, International journal of molecular medicine, 9(2) (2), 113 - 7, English, International magazine

  [Refereed]

  Scientific journal


• Prevention by long-term fermented miso of induction of colonic aberrant crypt foci by azoxymethane in F344 rats.

  Masayuki Ohara, Huimei Lu, Katsutomo Shiraki, Yoshiyuki Ishimura, Toshihiro Uesaka, Osamu Katoh, Hiromitsu Watanabe

  The present study was designed to investigate the effects of fermented miso in the diet on the induction of aberrant crypt foci (ACF) by azoxymethane (AOM) in male F344 rats. A total of 50 rats, 8 weeks of age, were divided into 5 groups and given weekly subcutaneous injections of AOM (15 mg/kg body wt) for 3 weeks. Rats were fed a normal control MF solid diet, or solid diet containing 10% long-term fermented (aged), medium- or short-term fermented miso, or 2.2% NaCl for 5 weeks, starting one week before the first AOM dosing. It was found that, compared to the control (MF) diet, the long-term fermented diet significantly decreased (by 22.2%) ACF/colon, but increased (by 18.2%) the number of aberrant crypts (Acs)/focus. The latter was also increased by the medium-term fermented diet (by 25.3%). The PCNA labeling index was only affected by the short-term fermented diet (36.9% increase) and by 2.2% NaCl diet (27.2% increased). The present results indicate that aged or completely fermented miso supplemented into the diet, could act as a chemopreventive agent for colon carcinogenesis.

  2002, Oncology reports, 9(1) (1), 69 - 73, English, International magazine

  Scientific journal


• Inhibition by long-term fermented miso of induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine in CD (SD) rats.

  Masayuki Ohara, Huimei Lu, Katsutomo Shiraki, Yoshiyuki Ishimura, Toshihiro Uesaka, Osamu Katoh, Hiromitsu Watanabe

  The present study was designed to investigate the effects of fermented miso in the diet on the induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in male CD (SD) rats. A total of 120 animals, 6 weeks of age, were divided into 6 groups and given MNNG (100 ppm) in the drinking water for 16 weeks. Starting 1 week before the carcinogen treatment the rats were fed a normal control MF solid diet, or the same diet containing 10% long-term fermented, medium- or short-term fermented miso, or 1% NaCl until the end of the MNNG exposure period. They were then maintained on the MF control diet and normal tap water until the autopsy time point at 52 weeks. The long-term fermented miso significantly reduced the size of the gastric tumors as compared with the other groups. The present results thus indicate that dietary supplementation with long-term fermented miso could act as a chemopreventive agent for gastric carcinogenesis.

  2002, Oncology reports, 9(3) (3), 613 - 6, English, International magazine

  Scientific journal


• Prevention of the development of preneoplastic lesions, aberrant crypt foci, by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male F344 rats.

  H Lu, T Uesaka, O Katoh, E Kyo, H Watanabe

  The modifying effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (MAK) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for three weeks to induce ACF and fed on diets containing 0, 1.25, 2.5 and 5.0% MAK for five weeks, starting one week before the first dose of carcinogen. MAK significantly and dose-dependently prevented the development of ACF, decreasing the total number of AC and inhibiting cyst formation. MAK (2.5 and 5.0%) also significantly reduced the longitudinal-cross section areas of colon epithelium. MAK in all doses significantly reduced the PCNA positive index, area of the germinal region and number of cells per half crypt. In an additional in vitro experiment, MAK inhibited anchorage-independent growth of several colon carcinoma cell lines. The present results thus indicate that dietary MAK could act as a preventive agent for colon carcinogenesis.

  2001, Oncology reports, 8(6) (6), 1341 - 5, English, International magazine

  Scientific journal


• Influence of concomitant miso or NaCl treatment on induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

  H Watanabe, T Uesaka, S Kido, Y Ishimura, K Shiraki, K Kuramoto, S Hirata, S Shoji, O Katoh, N Fujimoto

  Six-week old male Sprague-Dawley (CD) rats were treated with 100 ppm N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 16 weeks in their drinking water with control, miso or sodium chloride (NaCl) supplemented diets. All animals were autopsied 12 months after the beginning of the MNNG treatment. Despite higher intake of MNNG in the high dose miso and NaCl groups, the total tumor incidences were decreased compared to middle and lowest values. The glandular stomach adenocarcinoma incidences in the 10% and 5% miso groups were significantly decreased as compared to those in the 2.2% or 1.1% NaCl groups, with the same concentration of NaCl.

  1999, Oncology reports, 6(5) (5), 989 - 93, English, International magazine

  Scientific journal


• No susceptibility of colon tissue implanted into the glandular stomach of rats to N-nitroso-N-methylurea carcinogenesis.

  Y Ando, T Uesaka, S Kido, N Fujimoto, M Tatematsu, Y Ishimura, K Shiraki, S Hirata, K Kuramoto, S Shoji, O Katoh, H Watanabe

  The present study was undertaken to determine the response of colonic mucosa implanted into the stomach fundus in 6-week-old male F344 rats to oral administration of N-nitroso-N-methylurea (MNU). In graft + MNU, 15% animals had tumors in the implanted colon tissue whereas a 26% incidence of gastric tumors was observed for the pyloric mucosa. In MNU alone, 30% of rats demonstrated gastric tumors. In graft alone 10% of tumors were observed in the grafted site but none in the pylorus. Thus while graft tissue may intrinsically have an elevated risk of tumor development, no susceptibility to MNU was observed in the present study.

  1998, Oncology reports, 5(6) (6), 1373 - 6, English, International magazine

  Scientific journal


• Synergistic action of neuropeptide Y and adrenaline in the eel atrium.

  T Uesaka

  Aug. 1996, The Journal of experimental biology, 199(Pt 8) (Pt 8), 1873 - 80, English, International magazine

  Scientific journal

• Glial cell line-derived neurotrophic factor is a key regulator for the migration of enteric neural crest derivatives

  Toshihiro Uesaka, Hideki Enomoto

  2011, NEUROSCIENCE RESEARCH, 71, E66 - E67, English

  Summary international conference


• Bcl-xL-mediated rescue of aganglionosis in a mouse model for Hirschsprung disease

  Toshihiro Uesaka, Hideki Enomoto

  2009, NEUROSCIENCE RESEARCH, 65, S66 - S67, English

  Summary international conference


• Multiple roles of GDNF signaling in development of the enteric nervous system

  Toshihiro Uesaka, Hideki Enomoto

  2008, NEUROSCIENCE RESEARCH, 61, S40 - S40, English

  Summary international conference


• Cdx2 homeodomain protein regulates the expression of MOK, a member of the mitogen-activated protein kinase superfamily, in the intestinal epithelial cells.

  Toshihiro Uesaka, Noriko Kageyama

  Lead, 27 Aug. 2004, FEBS letters, 573(1-3) (1-3), 147 - 54, English, International magazine

  [Refereed]


• Damage of the mouse testis by tritiated water and 137Cs-gamma-rays.

  Shoji Kashiwabara, Naoki Kashimoto, Seigo Sanoh, Toshihiro Uesaka, Osamu Katoh, Hiromitsu Watanabe

  Tritiated water at 23.2, 46.3 or 92.5 MBq/animal and 137Cs-gamma-rays at 9.5 Gy (equivalent 370 MBq) or lower doses were administered to 6-week old male C3H/HeNCrj and C57BL/6NCrj mice, as well as F1 Crj: B6C3F1 (C3H x C57BL) progeny. Each set of six to ten animals were autopsied 30 days after the first irradiation. Testis weights were decreased dose dependently, relative values being highest in the C3H and lowest in the C57BL case, with B6C3F1 intermediate. Vacuolization in seminiferous tubules appeared in the 23.2 MBq group and increased with the dose. Focal pyknosis and karyomegaly were found at 46.3 MBq, while primary and secondary spermatocytes and spermatids disappeared with 92.5 MBq. Only a few spermatogonia and Sertoli cells remained after exposure to 9.5 Gy 137Cs-gamma-rays. Sizes of seminiferous tubules were decreased dose dependently, with no strain differences. When male B6C3F1 mice were irradiated with Cs-gamma-rays at 0.119 (equivalent 4.63 MBq tritiated water) or 2.38 Gy (equivalent 92.5 MBq tritiated water), body weights and size of the seminiferous tubules were decreased at both doses, and the larger dose also caused reduction of testis weight and abnormal sperm. However, all changes except for the alteration in weights had disappeared 1 month after the final irradiation. It is considered that the size of seminiferous tubules may be a good parameter for radiation damage in the testis.

  Sep. 2003, Hiroshima journal of medical sciences, 52(3) (3), 53 - 8, English, Domestic magazine


• Effects of weaning by surrogate mothers (ACI) on tumor development in SD rats treated with methylnitrosourea (MNU) and/or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).

  Katsuhisa Shiraki, Huimei Lu, Yoshimasa Ishimura, Shoji Kashiwabara, Toshihiro Uesaka, Osamu Katoh, Hiromitsu Watanabe

  In this experiment, methylnitrosourea (MNU) was administered, followed by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), to assess effects of surrogate mothering on tumor. One or two day old male SD pups were treated with or without 30 mg/kg body weight of MNU and nursed by SD or ACI surrogate mothers for 5 weeks. When 6-weeks-old they were then treated with 100 ppm MNNG or tap water for 16 weeks. The tumor incidence in the MNNG alone group was significantly lower than with MNU alone or MNU+MNNG (p < 0.01). Kidney or nerve tumors mainly developed in the MNU group, gastric tumors in the MNNG group, and the two combined in the MNU+MNNG group. The incidence and mean number of tumors did not significantly differ between the two weaning groups. However, mean survival time with the ACI surrogate mothers after treatment with MNU was increased as compared with the SD mother group. Cumulative development of tumors in the ACI surrogate mother group was also delayed (p < 0.05). Similar results were obtained with MNU+MNNG and MNNG alone. The present experiment suggested that tumor induction might be effected by components of the mother's milk.

  Sep. 2002, Hiroshima journal of medical sciences, 51(3) (3), 75 - 9, English, Domestic magazine


• High expression of MCL1 gene related to vascular endothelial growth factor is associated with poor outcome in non-Hodgkin's lymphoma.

  Ken Kuramoto, Akira Sakai, Kazushi Shigemasa, Yasuo Takimoto, Hideki Asaoku, Takako Tsujimoto, Kenji Oda, Akiro Kimura, Toshihiro Uesaka, Hiromitsu Watanabe, Osamu Katoh

  Jan. 2002, British journal of haematology, 116(1) (1), 158 - 61, English, International magazine


• Radioprotective effects of miso (fermented soy bean paste) against radiation in B6C3F1 mice: increased small intestinal crypt survival, crypt lengths and prolongation of average time to death.

  M Ohara, H Lu, K Shiraki, Y Ishimura, T Uesaka, O Katoh, H Watanabe

  The radioprotective effect of miso, a fermentation product from soy bean, was investigated with reference to the survival time, crypt survival and jejunum crypt length in male B6C3F1 mice. Miso at three different fermentation stages (early-, medium- and long-term fermented miso) was mixed in MF diet into biscuits at 10% and was administered from 1 week before irradiation. Animal survival in the long-term fermented miso group was significantly prolonged as compared with the short-term fermented miso and MF cases after 8 Gy of 60Co-gamma-ray irradiation at a dose rate of 2Gy min(-1). Delay in mortality was evident in all three miso groups, with significantly increased survival. At doses of 10 and 12 Gy X-irradiation at a dose rate of 4 Gy min(-1), the treatment with long-term fermented miso significantly increased crypt survival. Also the protective influence against irradiation in terms of crypt lengths in the long-term fermented miso group was significantly greater than in the short-term or medium-term fermented miso and MF diet groups. Thus, prolonged fermentation appears to be very important for protection against radiation effects.

  Dec. 2001, Hiroshima journal of medical sciences, 50(4) (4), 83 - 6, English, Domestic magazine


• High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin.

  Z Liu, T Uesaka, H Watanabe, N Kato

  Nov. 2001, International journal of oncology, 19(5) (5), 1009 - 14, English, International magazine


• Glucagon-like peptide isolated from the eel intestine: effects on atrial beating.

  T Uesaka, K Yano, S Sugimoto, M Ando

  Lead, Sep. 2001, The Journal of experimental biology, 204(Pt 17) (Pt 17), 3019 - 26, English, International magazine


• ZK7, a novel zinc finger gene, is induced by vascular endothelial growth factor and inhibits apoptotic death in hematopoietic cells.

  K Kuramoto, T Uesaka, A Kimura, M Kobayashi, H Watanabe, O Katoh

  15 Jan. 2000, Cancer research, 60(2) (2), 425 - 30, English, International magazine

  [Refereed]


• Gastric tumor induction by 1,2-dimethylhydrazine in Wistar rats with intestinal metaplasia caused by X-irradiation.

  H Watanabe, T Uesaka, S Kido, Y Ishimura, K Shiraki, K Kuramoto, S Hirata, S Shoji, O Katoh, N Fujimoto

  Nov. 1999, Japanese journal of cancer research : Gann, 90(11) (11), 1207 - 11, English, Domestic magazine


• Effects of eel neuropeptide Y on ion transport across the seawater eel intestine.

  T Uesaka, K Yano, S Sugimoto, M Ando

  A neuropeptide Y (eNPY) was isolated from the intestinal extract of eels. This peptide enhanced significantly the serosa-negative transepithelial potential difference (PD) and short-circuit current (Isc) across the intestine of the seawater eel after pretreatment with isobutylmethylxanthine, serotonin and methacholine. The effects of eNPY on the Isc were concentration-dependent with a threshold concentration of 3 x 10(-9) M and a maximal effect at 3 x 10(-7) M. Similar concentration-response curve was obtained by porcine peptide YY (pPYY). Since 9 amino acid residues are replaced in the pPYY, this result indicates that these substitutions do not change the potency and the efficacy. These stimulatory actions of eNPY were not blocked by tetrodotoxin, an inhibitor of neural firing, or yohimbine, an alpha 2-adrenoceptor antagonist, indicating that eNPY acts without enteric neural firing or catecholamine release. When eNPY and adrenaline (AD) were applied simultaneously, the effects were additive only at lower dosage (3 x 10(-8) M for eNPY, 3 x 10(-8) M for AD), but not at high dosage (10(-6) M eNPY, 10(-7) M AD). The ceiling effect at high dosage suggests that these two regulators act through common signal transduction systems and affect the Na(+)-K(+)-Cl- cotransport system, since both effects were completely blocked by bumetanide, a specific inhibitor of Na(+)-K(+)-Cl- cotransporter.

  Lead, Jun. 1996, Zoological science, 13(3) (3), 341 - 6, English, Domestic magazine

  [Refereed]


• Somatostatin-, vasoactive intestinal peptide-, and granulin-like peptides isolated from intestinal extracts of goldfish, Carassius auratus.

  T Uesaka, K Yano, M Yamasaki, M Ando

  Lead, Sep. 1995, General and comparative endocrinology, 99(3) (3), 298 - 306, English, International magazine


• Glutamate substitution for glutamine at position 5 or 6 reduces somatostatin action in the eel intestine.

  T Uesaka, K Yano, M Yamasaki, M Ando

  Isolating a new somatostatin-like peptide from eel gut, the active residues to potentiate somatostatin action in the eel intestine were determined. In the newly-isolated peptide, the 5th or 6th Gln of the eel somatostatin (eSS-25II) was replaced with Glu. Although this peptide also enhanced the short-circuit current (I_) across the intestine of the seawater eel, higher concentrations (approximately 30 fold) were required to obtain the same effects as eSS-25II. Since the I_ is due to active Cl^- transport, this indicates that a structure formed by Gln-Gln residues at position 5 and 6 potentiates the somatostatin action to enhance ion and water transport across the intestine of the eel.

  Zoological Society of Japan, Jun. 1994, Zoological science, 11(3) (3), 491 - 4, English, Domestic magazine

  [Refereed]


• Somatostatin-related peptides isolated from the eel gut: effects on ion and water absorption across the intestine of the seawater eel.

  T Uesaka, K Yano, M Yamasaki, K Nagashima, M Ando

  Mar. 1994, The Journal of experimental biology, 188, 205 - 16, English, International magazine

  [Refereed]


• Structure and function of a pentapeptide isolated from the gut of the eel.

  T Uesaka, T Ikeda, I Kubota, Y Muneoka, M Ando

  31 Oct. 1991, Biochemical and biophysical research communications, 180(2) (2), 828 - 32, English, International magazine

  [Refereed]

• Physiology of the Gastrointestinal Tract / Development of the Enteric Nervous System

  HeatherM.Young, LinconAStamp, Uesaka Toshihiro, MarleneM.Hao, DonalfE.Newgreen, HidekiEnomoto

  Others, Academic Press, 2018, English

  Scholarly book

• 腸管神経系の形成不全後のシュワン細胞系譜からの腸管ニューロン産生

  UESAKA TOSHIHIRO

  第124回日本解剖学会総会・全国学術集会, Mar. 2019, Japanese, 新潟, Domestic conference

  Oral presentation


• 腸管神経系の形成不全後のシュワン細胞系譜からの腸管ニューロン産生

  UESAKA TOSHIHIRO

  CSMIリトリート「若手道場」, Jan. 2019, Japanese, 淡路, Domestic conference

  Oral presentation


• RET 活性化型変異 C618F は遺伝子量減少によりヒルシュスプルング病を誘導する

  ITO KEISUKE, 岡本 光正, UESAKA TOSHIHIRO, 前田 貢作, ENOMOTO HIDEKI

  CSMIリトリート「若手道場」, Jan. 2019, Japanese, 淡路, Domestic conference

  Oral presentation


• Formation of enteric nervous system from Schwann cell precursors in mouse models of Hirschsprung disease

  UESAKA TOSHIHIRO

  第2回神戸理研・神戸大学合同シンポジウム, Jan. 2019, English, 神戸, Domestic conference

  Poster presentation


• 腸管神経系形成不全下におけるシュワン細胞系譜からのニューロン産生

  UESAKA TOSHIHIRO, ENOMOTO HIDEKI

  第94回日本解剖学会近畿支部学術集会, Nov. 2018, Japanese, 神戸, Domestic conference

  Oral presentation


• RET 活性化型変異 C618F は遺伝子量減少によりヒルシュスプルング病を誘導する

  ITO KEISUKE, 岡本 光正, UESAKA TOSHIHIRO, 前田 貢作, ENOMOTO HIDEKI

  第94回日本解剖学会近畿支部学術集会, Nov. 2018, Japanese, 神戸, Domestic conference

  Oral presentation


• 胎児期と生後における腸管神経系の形成

  UESAKA TOSHIHIRO

  第８回 Tokyo Vertebrate Morphology Meeting, Aug. 2018, Japanese, 東京, Domestic conference

  Invited oral presentation


• Formation of enteric nervous system from Schwann cell precursors in mouse models of Hirschsprung disease

  Toshihiro Uesaka

  Development of the Enteric Nervous System:cells,signals,genes and therapy 5th International Symposium, Apr. 2018, English, Boston, International conference

  Oral presentation


• Glial cell-based development and function of the enteric nervous system

  Enomoto Hideki, Uesaka Toshihiro

  第70回日本自律神経学会総会, Aug. 2017, English, 日本自律神経学会, 名古屋, International conference

  Oral presentation


• Enteric neurogenesis from Schwann cell lineage in models of Hirschsprung disease

  Uesaka Toshihiro, Enomoto Hideki

  第40回日本神経科学大会, Jul. 2017, English, 日本神経科学学会, 千葉, Domestic conference

  Oral presentation


• Enteric neurogenesis from Schwann cell lineage in mouse models of Hirschsprung disease

  Uesaka Toshihiro, Mayumi Nagashimada, Enomoto Hideki

  BMB2015, Dec. 2015, Japanese, 日本分子生物学会The Molecular Biology Society of Japan, 神戸, Domestic conference

  Poster presentation


• The impact of RET gain-of-function mutation on development of the enteric nervous system

  Mitsumasa Okamoto, Uesaka Toshihiro, Keisuke Itoh, Enomoto Hideki

  4th International Symposium on "Development of the enteric nervous system:Cells,Singnals,Genes and Therapy", Apr. 2015, English, ENS meeting scientific organizing committee:Robert Hofstra,Alan Burns(local organizer), Rotterdam, The Netherlands, International conference

  Poster presentation


• Neurogenesis from Schwann cell lineage in mouse models of Hirschsprung disease

  Uesaka Toshihiro, Mayumi Nagashimada, Enomoto Hideki

  4th International Symposium on "Development of the enteric nervous system:Cells,Singnals,Genes and Therapy", Apr. 2015, English, ENS meeting scientific organizing committee:Robert Hofstra,Alan Burns(local organizer), Rotterdam, The Netherlands, International conference

  Poster presentation


• Schwann cell precursor-like cells are a novel neuronal origin of the enteric nervous system

  Uesaka Toshihiro, Enomoto Hideki

  47th Annual Meeting for the Japanese Society of Development Biologists, May 2014, English, Japanese Society of Developmental Biologists, 名古屋, Domestic conference

  Oral presentation


• Schwann cell precursor-like cells from the mesentery are a cellular source of enteric neurons

  Uesaka Toshihiro, Enomoto Hideki

  Gordon Research Conferences Neural crest, Jul. 2013, English, Gordon Reserch Conference, Easton, USA, neural crest, International conference

  Poster presentation


• Schwann cell precursor-like cells from the mesentery are a cellular origin of enteric neurons

  Uesaka Toshihiro, Enomoto Hideki

  Neuro2013, Jun. 2013, Japanese, Japan Neuroscience Society, 京都, Cellular otigin, Domestic conference

  Poster presentation

• THE MOLECULAR BIOLOGY SOCIETY OF JAPAN


• JAPANESE SOCIETY OF DEVELOPMENTAL BIOLOGISTS


• THE JAPAN NEUROSCIENCE SOCIETY

• 黎明研究 「遺伝子導入による小腸放射線障害の軽減効果の検証」

  2003

• Postnatal neurogenesis in the pelvic viscera

  上坂 敏弘

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2024 - 31 Mar. 2027


• シュワン細胞による腸管神経系の再形成の誘導

  上坂 敏弘

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 01 Apr. 2021 - 31 Mar. 2024

  潜在的に腸管ニューロン産生能を有するシュワン細胞の特性を明らかにするために、シュワン細胞系譜の細胞を遺伝学的に標識するDesert hedgehog (Dhh)::CreERT2ドライバーを用いて、蛍光標識された細胞を腸管膜や腸管から回収を試みた。しかし、現時点では、一匹あたりから単離・回収される細胞数が少ないため、まだ遺伝子発現解析には至っていない。そこで最近報告されたマウスとヒトの単一細胞RNA-seqデータを用いてDhh陽性細胞の遺伝子発現プロファイルを解析した。その結果、マウスでは、Dhh遺伝子発現は腸管に入ると検出されないレベルに下がってしまうため、経時的な遺伝子発現変化などを追跡することが困難であることがわかった。そこで第一段階として、迷走神経堤由来の腸管グリア細胞とDhh陽性シュワン細胞系譜の細胞間で遺伝子発現を比較し、シュワン細胞系譜の細胞の有用な遺伝子マーカー候補のリストアップを進め、Dhh遺伝子に代わるマーカーの探索を進めている。また他の末梢神経系のシュワン細胞の単一細胞RNA-seqデータと比較して、シュワン細胞とは異なる遺伝子群についてもリストを作成している。一方で、ヒト胎児においては、Dhh陽性細胞が腸管においてしばらくの間検出されるため、経時的な追跡が可能であることがわかった。ヒトDhh陽性細胞群データを解析したところ、シュワン細胞様細胞、Nestin陽性細胞、bipotent（ニューロン・グリア）様の三つのクラスターに分類できた。さらに迷走神経堤由来の細胞と比較し、ニューロン産生能の活性化に関わる分子群の探索に活用していく。


• 腸管神経系の組織恒常性維持機構の解明

  上坂 敏弘

  科学研究費補助金／新学術領域研究, Apr. 2017 - Mar. 2019, Principal investigator

  Competitive research funding


• RETチロシンキナーゼの活性化レベル変動と神経系形成異常の相関についての検証

  上坂 敏弘

  学術研究助成基金助成金／基盤研究(C), Apr. 2016 - Mar. 2019, Principal investigator

  Competitive research funding


• 神経芽腫に対する新規治療剤の探索

  榎本 秀樹

  国立研究開発法人日本医療研究開発機構, 創薬支援推進事業・創薬総合支援事業, 2017

  Competitive research funding


• Vascular tissues that supports migration of enteric neural progenitors

  ENOMOTO HIDEKI, UESAKA Toshihiro, ITO Keisuke

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), 01 Apr. 2010 - 31 Mar. 2015

  In this study we conducted cellular and molecular analyses on neuro-vascular interactions in the development of the enteric nervous system (ENS). By performing live-cell imaging of enteric neural progenitors and vasculature in mice, we examined cell behavior in developing ENS. We have discovered that a subset of enteric neural progenitors crosses the mesentery when the small and large intestines are juxtaposed to each other during development. Trans-mesenteric enteric neural progenitors are the principal source of the ENS in the colon, and impaired trans-mesenteric migration delays colonization of the colon by enteric neural progenitors. Moreover, trans-mesenteric enteric progenitors are reduced in a mouse model of Hirschsprung disease (HSCR: congenital absence of the ENS in the distal gut), suggesting a potential involvement of impaired trans-mesenteric migration in HSCR pathogenesis. We have also discovered that GDNF is one of the molecules that regulate trans-mesenteric migration.


• 腸神経系におけるニューロン新生の新たな細胞ソースの同定とその生理的意義の解明

  上坂 敏弘

  文部科学省, 科学研究費補助金(基盤研究(C)), 2013 - 2015, Principal investigator

  Competitive research funding


• Understanding the mechanisms underlying the pathogenesis of Hirschsprung disease

  Toshihiro UESAKA

  Ministry of Education, Culture, Sports, Science and Technology, Grants-in-Aid for Scientific Research(基盤研究(C)), Grant-in-Aid for Scientific Research (C), The Institute of Physical and Chemical Research, 2008 - 2010, Principal investigator

  RET tyrosine kinase is required for the development of the enteric nervous system (ENS). Hypomorphic RET alleles cause intestinal aganglionosis [Hirschsprung disease (HSCR)]. We have shown that elevated expression of Bcl-xL inhibits ENS precursor death in both Ret-null and hypomorphic states. Moreover, the prevention of cell death allows morphologically and functionally normal ENS formation in Ret-hypomorphic mice. These results indicate that ENS precursor death is a principal cause of intestinal aganglionosis in a Ret hypomorphic state, and suggest that the inhibition of cell death is a ro...

  Competitive research funding


• 腸管神経と腎臓の発生過程の動的観察とGDNFシグナルの役割の解明

  上坂 敏弘

  文部科学省, 科学研究費補助金(若手研究(B)), 2006 - 2007, Principal investigator

  神経堤細胞が腸管全体に移行し、神経分化をすでに開始しているマウス胚15.5日目にGDNF受容体を条件的ノックアウトしたところ、結腸遠位部以降において36時間以内に神経網が消失することを見いだした。つまり、生体内でGDNFシグナルが腸神経細胞の生存に必須であることを初めて示したことになる。ヒルシュスプルング病における腸管壁内神経節細胞の先天的欠損は神経堤細胞の移行異常によるものと従来考えられてきたが、我々の研究により、GDNF/RETシグナルの減少による神経細胞死の可能性が新たに出てきた。そこで、Ret遺伝子変異によるヒルシュスプルング病モデルマウスを作製し、細胞死の有無を検証した。我々は、マウスにおいてRETチロシンキナーゼの発現を通常の約30%に下げることで、従来のRetノックアウトマウスと異なり、腎臓やモーターニューロンの発生異常は認められず、結腸遠位部以降の腸神経の欠損が認められ、またこの異常の発症率がオスに高い傾向がみられる

  Competitive research funding


• 腸管神経の発生に関する研究

  2004

  Competitive research funding


• Study on the development of the enteric nervous system

  2004

  Competitive research funding


• 小腸放射線障害治療に向けて上皮細胞の分化と再生に関与する遺伝子の研究

  上坂 敏弘

  文部科学省, 科学研究費補助金(若手研究(B)), 2002 - 2003, Principal investigator

  主に腸で発現する転写調節因子Cdx2に着目し、Cdx2の標的遺伝子を明らかにしていくことによって、腸上皮細胞の細胞増殖、分化制御、さらには細胞死制御機構の解明と分化マーカーの同定を目指した。Cdx2の発現制御が可能なラット胎児由来未分化腸上皮細胞株IEC-6 Tet-Off/Cdx2を用いて、Cdx2の発現誘導に伴い転写促進もしくは転写抑制される遺伝子をオリゴヌクレオチド・マイクロアレイ(CodeLink UniSet Rat I Bioarray, Amersham)を用いて9,906種の遺伝子について調べた。現在23種類の遺伝子がCdx2によって発現上昇してくることをRT-PCRによって確認している。これらの内、ゲノム情報がわかっているものに関しては、プロモーター領域と予想される上流域においてCdx2結合部位配列(TTTAC/T)の検索を行った。この結果をもとに、ルシフェラーゼを用いたプロモーターアッセイ、ゲルシフトアッセイ、クロマチン沈降法を行い、Cdx2によって直接転写調節されることを確認した。これにより、転写調節因子E2F3、17

  Competitive research funding


• アポトーシス抑制遺伝子MCL1の転写調節機構に関する研究

  加藤 修, 上坂 敏弘

  日本学術振興会, 科学研究費助成事業, 特定領域研究(C), 広島大学, 2000 - 2000

  放射線や抗がん剤によるがん細胞のアポトーシスを血管内皮細胞増殖因子(VEGF)のような細胞増殖因子が抑制すること、その分子機序のひとつとしてアポトーシス抑制作用を持つmcl1遺伝子の発現誘導が関与していることを我々はすでに明らかにしている(Katoh,o.et al,Cancer Res,55:5687-5692,1995;Katoh,o.et al,Cancer Res,58:5565-5569,1998)。また、放射線や抗がん剤に曝露されることによりmcl1遺伝子が発現誘導されることも知られている。mcl1遺伝子はbcl2ファミリーに属し、その遺伝子産物はアポトーシス抑制作用を持っている。がん細胞において放射線や抗がん剤曝露あるいは細胞増殖因子刺激によりmcl1遺伝子は、そのmRNA発現が誘導され、がん細胞の細胞死の抑制すなわち生存維持に働き、最終的にはがん治療に対する耐性獲得に関与している。上記した種々のストレスや刺激に対するmcl1遺伝子の転写調節機構を明らかにすることを目的として本研究を行った。マウスmcl1遺伝子5'側上流域の約1.2kbのDNAをクローニングし、塩基配列を決定した。さらに放射線曝露や細胞増殖因子刺激によるmcl1遺伝子の転写調節領域を明らかにするために、レポーターアッセイをおこなった。その結果、マウス白血病細胞株32Dあるいは血管内皮細胞株PmTc-1いずれを用いても放射線曝露刺激においては翻訳開始点から上流-256から-406の領域が活性上昇に重要であることが明らかになった。さらに血管内皮細胞増殖因子(VEGF)刺激においても同じ領域が活性上昇に重要であることを確認した。mcl1遺伝子の転写調節にはこの領域に結合する転写因子が関与している可能性が示唆された。