| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
The molecular mechanisms governing eosinophil development remain largely unknown. In this study, we analyzed roles of transcription factors, C/EBP, GATA and RFX in this process. We retrovirally transduced these transcription factor genes into human CD34-positive hematopoietic progenitors and analyzed the effects of transduced genes on the cell differentiation. A dominant negative C/EBP completely blocked the granulocyte/macrophage commitment of human myeloid progenitors. Alternatively, Langerhans cell (LC) commitment was markedly facilitated in the absence of TNFα, a strong inducer of Langerhans cell development. Conversely, expression of wild-type C/EBP myeloid progenitors promoted eosinophilic differentiation and completely inhibited TNFα-dependent LC development. On the other hand, enforced expression of GATA-1 in human primary myeloid progenitor cells completely switched myeloid cell fate into eosinophils. Expression of GATA-1 exclusively promoted development and terminal maturation of eosinophils. Importantly, GATA-1-deficient mice failed to develop eosinophil progenitors in the fetal liver. Additionally, GATA-2 also showed instructive capacity comparable to GATA-1 vitro and efficiently compensated for GATA-1-deficiency in terms of eosinophil development in vivo, indicating that proper accumulation of GATA factors is critical for eosinophil development. All these data clearly show that the expression of GATA-1 in combination with C/EBPα could be the critical determinant for eosinophil lineage commitment.
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