| Project/Area Number |
14104024
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Developmental biology
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| Research Institution | National Institute of Genetics |
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Principal Investigator |
SAGA Yumiko National Institute of Genetics, Division of Mammalian Genetics, Professor, 系統生物研究センター, 教授 (50221271)
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| Co-Investigator(Kenkyū-buntansha) |
KOKUBO Hiroki National Institute of Genetics, Assistant Professor, 助手 (10270480)
TAKAHASHI Yu National Institute of Health Sciences, Division of Cellular and Molecular Toxicology, senior researcher, 毒性部, 主任研究官 (60321858)
KITAJIMA Satoshi National Institute of Health Sciences, Division of Cellular and Molecular Toxicology, Section Chief, 毒性部, 主任研究官 (30270622)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥113,230,000 (Direct Cost: ¥87,100,000、Indirect Cost: ¥26,130,000)
Fiscal Year 2006: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2005: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2004: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2003: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2002: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000)
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| Keywords | Mesp1 / Mesp2 / Hesr1 / Hesr2 / heart formation / somitogenesis / Notch signaling / segmentation clock / 房室境界 / EphA4 / Ripply2 / Notchシグナル系 / hesr1 / hesr2 / GFP |
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| Research Abstract |
We tackled two major objectives concerning mouse organogenesis derived from mesodermal cells. One is heart morphogenesis and the other is somitogenesis.
1.Heart morphogenesis
1)We generated Mesp1, Mesp2 double-knockout ES cells and found that the ES cells were unable to differentiate cardiac cells. The downstream target genes were analyzed by microarray analyses.
2)We found that the forced expression of Hesr1 or Hesr2 in the entire cardiac lineage results in the reduction or loss of the atrioventricular (AV) canal. The following molecular analyses revealed that Hesr1 and Hesr2 play crucial roles in AV boundary formation through suppression of Tbx2 expression.
2.Somitogenesis
1)Through enhancer analysis of Mesp2 gene, we revealed that a novel mechanism, via Tbx6-dependent Notch signaling, acts on the transcriptional regulation of Mesp2.
2)We succeeded in visualization of the Mesp2 protein by generating Mesp2-venus knockin mouse, which indicates that the anterior border of the Mesp2 expression domain defines the next segmental border.
3)We also succeeded visualization of Notch activity together with Mesp2 protein and we found that Notch signal was suppressed by Mesp2 function, by which segmental border is finally defined.
4)We found that Mesp2 directly binds to the enhancer sequence of EphA4. Furthermore, the forced expression of Mesp2 in somitic cells results in the activation of EphA4 and repression of the caudal gene Uncx4.1. In addition, ectopic Mesp2 expression induced abnormally epithelialized structures, which supported to the idea that Mesp2 induces the formation of segmental borders by activating genes, which play roles in cellular epithelialization.
5)We also find that a transcriptional repressor Ripply2 is under the control of Mesp2 and plays a role in the segmentation process via mainly suppressing Mesp2 expression.
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