2006 Fiscal Year Final Research Report Summary
Dosage requirement of transcription factors in the differentiation of pancreatic endocrine & exocrine cells
| Project/Area Number |
18390059
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General anatomy (including Histology/Embryology)
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| Research Institution | Kyoto University |
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Principal Investigator |
KAWAGUCHI Yoshiya Kyoto University, Kyoto University Medical School Dep. of Hepato-Bilially, Pancreatic Surgery & Transplantation, Assistant Professor (60359792)
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| Project Period (FY) |
2006 – 2007
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| Keywords | ptfla / differentiation / cell fate determination / transcription factor / pancreatogenesis / cholangiogenesis / Notch / diabetsa |
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| Research Abstract |
Embryonic cells possess some plasticity that can respond to environmental or internal changes, resulting in other cell fate choice. Using Cre/loxp based genetic lineage tracing combined with gene KO strategy, we have previously shown that ptfla plays as "pancreatic determiner" during organogenesis. Expression of the key gene seems to determine the fate of undifferentiated cells, but its dosage control remained unknown. We demonstrate that Hesl-mediated Notch signal suppresses the ptfla expression whereby represses the ectopic pancreas formation in other organs. Site specific formation of ectopic pancreatic tissues in the stomach, duodenum and the bile duct observed in Hesl KO mice suggested the unidentified positive regulator of ptfla. These finding support the hypothesis that fate determination of undifferentiated endodermal cells of the foregut depends on the dosage of the key transcriptional factors including ptfla. Mice experiments crossing several hypomorphic alleles of ptfla combined with lineage tracing, we showed that the reduced dosage of ptfla results in (1)misspecification into duodenal and bile duct cells, (2)exocrine differentiation is extremely delayed but the timing of endocrine differentiation is normal, (3)hypomorphic mutants showed pancreatic hypoplasia and disturbed pancreatic function including exocrine dysfunction and diabetes. These results indicate that "plasticity" of the embryonic cells is explained by the dosage control of transcriptional factors in cell fate choice and that ptfla plays as cell fate determiner in two steps: in the specification of pancreatic progenitors and in the exocrine cell fate choice. Our findings predict the possible involvement of ptfla in the neonatal diabetes; SNIPs or mutation in its regulatory sequence may cause diabetes.
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[Journal Article] Reduction of Ptfla gene dosage causes pancreatic hypoplasia and diabetes in mice.2008
Author(s)
Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Kawaguchi M, Terao M, Doi R, Wright CV, Hoshino M, Chiba T, Uemoto S.
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Journal Title
Diabetes. 57
Pages: 2421-31
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Reduction of Ptfla gene dosage causes pancreatic hypoplasia and diabetes in mice.2008
Author(s)
Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Kawaguchi M, Terao M, Doi R, Wright CV, Hoshino M, Chiba T, Uemoto S.
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Journal Title
Diabetes. 57(9)
Pages: 2421-31
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Rbp-j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse deve lopment.2007
Author(s)
Fujikura J, Hosoda K, Kawaguchi Y, Noguchi M, Iwakura H, Odori S, Mori E, Tomita T, Hirata M, Ebihara K, Masuzaki H, Fukuda A, Furuyama K, Tanigaki K, Yabe D, Nakao K.
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Journal Title
Dev Dyn. 236
Pages: 2779-91
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Rbp-j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse development.2007
Author(s)
Fujikura J, Hosoda K, Kawaguchi Y, Noguchi M, Iwakura H, Odori S, Mori E, Tomita T, Hirata M, Ebihara K, Masuzaki H, Fukuda A, Furuyama K, Tanigaki K, Yabe D, Nakao K.
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Journal Title
Dev Dyn. 236(10)
Pages: 2779-91
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Ectopic pancreas formation in Hesl-knockout mice reveals piasticity of endodermal progenitors of the gut, bile duct, and pancreas.2006
Author(s)
Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Koizumi M, Boyer DF, Fujimoto K, Doi R, Kageyama R, Wright CV, Chiba T.
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Journal Title
J Clin Invest. 116
Pages: 1484-93
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation.2006
Author(s)
Miyatsuka T, Kaneto H, Shiraiwa T, Matsuoka TA, Yamamoto K, Kato K, Nakamura Y, Akira S, Takeda K, Kajimoto Y, Yamasaki Y, Sandgren EP, Kawaguchi Y, Wright CV, Fujitani Y.
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Journal Title
Genes Dev. 20
Pages: 1435-40
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Ptfla determines horizontal and amacrine cell fates during mouse retinal development.2006
Author(s)
Fujitani Y, Fujitani S, Luo H, Qiu F, Burlison J, Long Q, Kawaguchi Y, Edlund H, MacDonald RJ, Furukawa T, Fujikado T, Magnuson MA, Xiang M, Wright CV.
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Journal Title
Development. 133
Pages: 4439-50
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Ectopic pancreas formation in Hesl -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas.2006
Author(s)
Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Koizumi M, Boyer DF, Fujimoto K, Doi R, Kageyama R, Wright CV, Chiba T
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Journal Title
J Clin Invest. 116(6)
Pages: 1484-93
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation2006
Author(s)
Miyatsuka T, Kaneto H, Shiraiwa T, Matsuoka TA, Yamamoto K, Kato K, Nakamura Y, Akira S, Takeda K, Kajimoto Y, Yamasaki Y, Sandgren EP, Kawaguchi Y, Wright CV, Fujitani Y.
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Journal Title
Genes Dev. 20(11)
Pages: 1435-40
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Ptfla determines horizontal and amacrine cell fates during mouse retinal development.2006
Author(s)
Fujitani Y, Fujitani S, Luo H, Qiu F, Burlison J, Long Q, Kawaguchi Y, Edlund H, MacDonald RJ, Furukawa T, Fujikado T, Magnuson MA, Xiang M, Wright CV.
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Journal Title
Development. 133(22)
Pages: 4439-50
Description
「研究成果報告書概要(欧文)」より
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