2000 Fiscal Year Final Research Report Summary
Roles of Wnt/β-catenin/TCF signal transduction pathway in early T cell development
| Project/Area Number |
10670299
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
FUJIMOTO Shinji KYOTO UNIVERSITY, Institute for Frontier Medical Sciences, Assistant, 再生医科学研究所, 助手 (60199370)
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| Project Period (FY) |
1998 – 2000
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| Keywords | murine early T cell development / Wnt / Frizzled 3 / dominant negative form / retroviral vector / signal transduction |
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| Research Abstract |
Wnt/β-catenin/TCF signaling is important for murine early T cell development. However, our understanding of each transmitting molecule is incomplete. As the result of this study, a member of the Frizzled (Fz) family, Fz3, to which secreted Wnt protein binds, is revealed to be one of key factors in the pathway. I have also established a method efficiently transducing gene into murine hematopoietic progenitors.
The expression level of Fz genes in fetal and adult thymus was examined by RT-PCR.We found that Fz3 is exclusively transcribed in fetal thymocytes, and that the highest expression is observed at the developmental stage after which rearrangement of T cell receptor (TCR) β chain gene occurs. In order to investigate the function of Fz3 during early T cell development, a dominant negative form retaining only Fz3 extracellular domain (sFz3) was forced to express in hematopoietic progenitors and the cells were cultured under the conditions suitable for T cell development. For the transduction, a retroviral vector with GFP gene as a marker was used. The number of cells recovered after the culture was far less than that obtained from the vector-transduced sample. Surprisingly, immature CD3^-CD4^-CD8^-CD44^-CD25^+ T cells still existed in the sFz3-transduced sample. Additionally, Fz3 is not expressed in TCR^+ T cells. Taken together, my data strongly suggest that the signal mediated by Fz3 is indispensable for differentiation and proliferation of T progenitors which rearranged TCR β but not α chain gene, and that the signal is partly responsible for multiplying more primitive T progenitors with unrearranged TCR β chain loci. In the future, Wnt molecules that bind to Fz3 in the T progenitors should be determined. In addition, analysis of target genes regulated by the Fz3 signaling will be required to comprehend the molecular mechanisms of early T cell development.
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[Publications] Ohmura, K., Kawamoto, H., Fujimoto, S., Ozaki, S., Nakao, K.and Kastura, Y.: "Emergence of T, B, and myeloid lineage-committed as well as multipotent hematopoietic progenitors in the aortagonad-mesonephros region of day 10 fetuses of the mouse."J.lmmunol.. 163. 4788-4795 (1999)
Description
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