| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Molecular mechanisms regulating self-renewal and differentiation of hematopoietic stem cells (HSCs) remain elusive. Translin was originally identified as a unique protein recognizing consensus sequences at chromosome breakpoint junctions in human lymphoid neoplasms. Here we generated mice homozygous for an inactivating mutation of the whole Translin gene and showed that this results in blocked development of multiple lineages of the hematopoietic system. First, young Translin^<-/-> mice display markedly reduced lymphocyte counts in the peripheral blood, attributable to the developmental arrest of B-lymphocytes in the earliest progenitor stage (B220^- CD43^+ IL-7R^+). Second, aged mutant mice, however, exhibited progressive bone marrow failure, with a lack of immature myeloid lineage cells. The decrease in the number of immature myeloid cells might be due to increased apoptosis. Therefore, we compared the extent of apoptosis in the bone marrow cells of control and Translin^<-/-> mice by
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TUNEL staining. The data showed no significant difference in the staining between the bone marrow cells of control and Translin^<-/-> mice. To determine whether these mice have defect in the generation of progenitors, we investigated the expression of PU.1 that has previously been suggested to be essential for myeloid development. However, quantitative RT-PCR analysis showed PU.1 mRNA to be expressed at equivalent levels in bone marrows of aged Translin^<-/-> and Translin^<+/+> mice, in contrast, to marked reduction of E47 expression in the Translin^<-/-> case. We also found that the mRNA level of the bHLH oncoprotein TAL1, shown to heterodimerize with the E47 bHLH region in vitro and in vivo, was remarkably reduced in bone marrow of mutant mice. On the contrary, the number of HSCs (Lin^-, Scal^+, c-kit^+) was remarkably increased in the bone marrow of mutant mice. Our results indicate that Translin restricts both self-renewal and multilineage differentiation of HSCs possibly affecting hematopoietic microenvironment. Less
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