| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2005: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
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| Research Abstract |
Blood cells are produced immature hematopoietic cells through commitment and maturation. Gene targeting analyses have revealed that various transcription factors are involved in the process. However, molecular functions of the factors remain unclear. In this stud, using the combination of in vitro differentiation from mouse embryonic stem cells (ES cells) to blood cells on OP9 stroma cells (OP9 system), and loss or gain of function of the transcription factors, roles of the factors such as GATA-1, GATA-2, Runx-1, and FOG-1 were analyzed.
All of the factors examined showed that their functions on hematopoietic differentiation was dependent on the context of the cell diffrentiation. In other words, individual transcription factors and co-factors' function was different at different differentiation stages. For example, erythroid specific transcription factor, GATA-1, was essential for proliferation and differentiation at early and late erthropoiesis, respectively.
One notable result is the self-renewal and multi-lineage differentiation ability of GATA-1 null proerythroblasts. We found that GATA-1-null proerythroblasts could survive and proliferate on OP9 stroma cells in the presence of erythropoietin. Furthermore, myeloid and mast cells were induced from the GATA-1-null proerythroblasts by the stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), respectively, but lymphoid differentiation was not achieved by in vivo transfer. Thus, without activity of the transcription factor required for terminal differentiation, even relatively mature and committed cells proliferate continuously with the differentiation capacity to other lineages. This data suggest that GATA-1 is a critical transcription factor to fix erythroid progenitors to the erythroid lineage.
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