Identification of genes which are involved in the development and transdifferentiation of hematopoietic stem cells

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In this investigation, we attempted to elucidate how hematopoietic stem cells are developed from AGM region of mouse embryos, and which factors are involved in the recruitment of bone marrow stem cells to injured organs First, we identified a set of genes which are expressed in purified bone marrow-derived hematopoietic stem cells, but not in hemangioblasts derived from differentiated ES cells. They included SHP1, c-mpl, Norel, and unknown gene S76. S76 mRNA is predominantly expressed in hematopoietic tissues in adult mice and encoded a membrane protein. RNAi mediated r repression of S76 mRNA in hematopoietic progenitor cells inhibited their growth, and augmented proliferative capacity of mast cell line, suggesting that S76 could be a novel regulator of cytokine-responsiveness in blood cells. On the other hand, we identified a novel protease RAMP and chemokine BRAY, both of which are up-regulated in muscular dystrophy mutant mice, mdx. RAMP and BRAK are expressed in skeletal muscle and brain, and associated in the process of muscle regeneration. In order to clarify in vivo roles of these secreted proteins, we newly generated transgenic and knock-out mouse lines. In addition to above described researches, we discovered novel roles of Meis3 and Runx1, and performed gene profiling studies of ovary and uterus, naturally-remodeling tissues. Although we only obtained clues, future studies by using genetically modified mice would provide a new paradigm for the development and transdifferentiation of hematopoietic stem cells.