2002 Fiscal Year Final Research Report Summary
Developmental Program and Genetic Disease by Six family genes.
| Project/Area Number |
12470029
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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 medical chemistry
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| Research Institution | Jichi Medical School |
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Principal Investigator |
KAWAKAMI Kiyoshi Jichi Medical School, Dept.of Medicine, Professor, 医学部, 教授 (10161283)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Keiko Jichi Medical School, Dept.of Medicine, Assistant Professor, 医学部, 講師 (10265241)
SATO Shigeru Jichi Medical School, Dept.of Medicine, Assistant Professor, 医学部, 講師 (70306108)
OZAKI Hidenori Jichi Medical School, Dept.of Medicine, Research Associate, 医学部, 助手 (70296094)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Six / Eya / Dach / myotonic dystrophy (DM1) / target genes / gene defective mice / organogenesis / cooperative action |
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| Research Abstract |
This study aims to reveal roles of Six family genes in development, to elucidate gene network including Six and involvement of Six genes in pathology of myotonic dystrophy (DM1). We performed analyses of Six gene defective mice, screening of target genes of Six proteins and analyses of molecular function of Eya and Dach protein that are cooperative factors of Six protein.
1 Six4/Six5 double knockout mice die within several hours after birth but we could not find any apparent anatomical anomalies. Six1 gene defective mice die just after birth and showed defective formation of inner ear, nose, kidney and thymus. The morphological abnormalities were noted from E10-11. Six1 gene is suggested to be essential for the formation of these organs.
2 Target genes of Six5 proteins were identified. Transcription factors, signaling molecules and its receptors that are expressed during mesoderm differentiation were identified as putative target in P19 cells. Transcription factors and signaling molecules in nervous systems, transporters and receptor proteins of neural transmitters. In myoblasts, genes including myogenin, myosin, troponin, acetylcholine receptors that arespecific to skeletal muscle were identified. In lens epithelial cells, genes that had been shown to be involved in cataractogenesis were identified. It is suggested that altered regulation of these target genes leads to some symptoms of DM1.
3 We revealed that cooperative activation by GAL4-Eya and Dach is mediated through CBP. CBP bound to an immobilized chromatin template only in the presence of both GAL4-Eya and Dach. We also found that Dach can bind to chromatin as well as DNA regardless of the presence of GAL4-Eya protein. The binding affinity to chromatin was higher than that to naked DNA. The conserved DD1 domain of Dach is responsible for the DNA binding activity.
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