2001 Fiscal Year Final Research Report Summary
Identification of neuroblastoma associating genes and application of medical treatment using gene manipulation in an individual
| Project/Area Number |
12470164
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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 |
Pediatrics
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| Research Institution | Tohoku University |
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Principal Investigator |
HAYASHI Yutaka Tohoku University, School of Medicine, Professor, 大学院・医学系研究科, 教授 (40125638)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Megumi Tohoku University, Hospital, Lecturer, 医学部附属病院, 講師 (50282067)
NODA Tetsuo Tohoku University, School of Medicine, Professor, 大学院・医学系研究科, 教授 (10183550)
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| Project Period (FY) |
2000 – 2002
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| Keywords | neural crest / neuroblastoma / conditional knockout / Wnt signal / apoptosis |
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| Research Abstract |
During development of the neural crest (NC), which is the origin of neuroblastoma, Wnt signaling is also known to regulate cell expansion and/or determination of cell fate. To elucidate the function in the NC development, ape deficient mice and transgenic mice expressing activated beta-catenin specifically in the mouse NC were generated by using the conditional gene targeting method.
These mutant mice exhibited severe craniofacial defects including skull bone malformation and died around birth. Some of them had ventricular septum defects and persistent truncus arteriosus. At 11.5 dpc, UNEL staining revealed a significant increase in the number of apoptotic cells in the ventral craniofacial mesenchyme (VCM), the first bronchial arch (1st BA) and cardiac outflow tract (COT) in both mice. Both mutant embryos showed significant accumulation of beta-catenin in VCM, 1st BA and COT, where TUNEL positive cells were clustered. Therefore, it is likely that deregulated expression of beta-catenin may play a crucial role in the induction of apoptosis in cephalic and cardiac NC derived cells in the mutants mice. However, it is suggested that this apoptosis is not mediated by p53 from the analyses of Apc / p53 double deficient mice and activated beta-catenin / p53 null mice.
For further understanding of Wnt signaling in NC, NC specific beta-catenin conditional knockout mice were generated. These mutant mice were not embryonic lethal, but died immediately after birth. All mutants also suffered craniofacial defects, which were more severe than those in Apc mutants. Detailed examination showed these phenotype-might result from the disorder of cranial NC cell proliferation and/or the increase of apoptotic cells, and beta-catenin is essential in the development of cranial NC cells. No obvious malformation of heart suggested beta-catenin may be unnecessary in the development of cardiac NC cells.
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