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, 医学研究科, 助教 (60359792)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥8,330,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥930,000)
Fiscal Year 2007: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
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| Keywords | ptfla / differentiation / cell fate determination / transcription factor / pancreatogenesis / cholangiogenesis / Notch / diabetsa / Notch / 糖尿病 / 内胚葉 / 可塑性 / 発現量 |
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| Research Abstract |
本研究では膵細胞分化における転写因子ptfla発現量の役割を明らかにする目的で、Ptfla遺伝子下流領域を欠失したptfla cbllアリルとptflaにcreをノックインしたptfla creアリルを用い、ptfla (wt/wt), ptfla (cre/wt), ptfla (cbll/cbll), ptfla (cre/cbll)マウスを解析した。胎生12.5日のptfla発現量はそれぞれ1:0.55:0.32:0.14であった。出生時の膵サイズはwt/wtとcre/wtでは差がなかったが、cbll/cbllとcre/cbllは小さく、生後はその順番で発育遅延を生じた。ptflaはdose dependentに膵上皮の増殖を促進し、低発現マウスでは胎生期の膵管様上皮のbranchingと外分泌細胞分化が遅延したが、内分泌細胞分化は正常のタイミングで起こった。lineage tracingでは、一部のptfla低発現細胞は十二指腸上皮細胞と胆管上皮細胞へと運命変更していた。以上で、ptfla発現量が、(1)膵前駆細胞と胆管・十二指腸前駆細胞のレベルと(2)膵内分泌・外分泌細胞分化のレベルで、2段階の運命選択を担う事を示した。興味深いことに、内分泌細胞分化が正常のタイミングで起こるにもかかわらず、cbll/cbllとcre/cbllマウスではインシュリン産生細胞数が少なく、生後糖尿病を発症した。インシュリン産生を開始する時点でptflaの発現は無くなることから、前駆細胞プールの減少が原因と考えられる。この事は、ptflaのSNIPがヒト新生児糖尿病の原因となり得ることを示唆している(論文投稿済・revise中)。
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Report
(3 results)
Research Products
(33 results)
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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
Related Report
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
Related Report
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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
Related Report
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
Related Report
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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
Related Report
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
Related Report
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
Related Report
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
Related Report
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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
Related Report
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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
Related Report
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