| Co-Investigator(Kenkyū-buntansha) |
NOBUHISA Ikuo Kumamoto University Institute of Molecular Embryology and Genetics, Research Associate, 発生医学研究センター, 助手
NAKASHIMA Kinichi Kumamoto University Institute of Molecular Embryology and Genetics, Associate Professor, 発生医学研究センター, 助教授 (80302892)
松尾 律子 東京医科歯科大学, 難治疾患研究所, 助手 (00126260)
加藤 博明 東京医科歯科大学, 難治疾患研究所, 助手 (10152737)
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| Budget Amount *help |
¥11,400,000 (Direct Cost: ¥11,400,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Research Abstract |
gp130 is a signal-transducing receptor component shared by the interleukin-6 (IL-6) family of cytokines, i.e. IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and cardiotrophin-1 (CT-1). In this project, we have found that mice deficient for gp130 exhibit loss of motor neurons in the spinal cord, nucleus ambiguus and facial nucleus as well as sensory neurons in the dorsal root ganglions. The loss of neurons in the gp130 knock-out mice is prominent on embryonic day 18.5 but not 14.5, suggesting that gp130 is important for the survival and maintenance of neurons but not their differentiation. We have also found that signals from gp130 and bone morphogenetic protein (BMP) receptors act in synergy on fetal brain neural progenitor cells to induce astrocyte differentiation. For instance, LIF and BMP2 synergistically induce astrocytes in cultured neuroepithelial cells. The molecular basis proposed by us is that respective downstream transcription factors, STAT3 and Smads, form a complex bridged by a transcriptional coactivator p300. Another recent finding is that BMP2 inhibits neurogenesis from neural progenitor cells by upregulating expression of negative helix-loop-helix (HLH) factors, Id1, Id3 and Hes-5, which are capable of inhibiting transcriptional activity of neurogenic HLH transcription factors, Mash1 and Neurogenin. In this project, we have also found that MH60 hybridoma cells, which show gp130-signal dependent growth, undergo apoptosis in response to BMP2. Unexpectedly, BMP2-mediated apoptosis is blocked by ectopic expression of inhibitory Smad species, Smad6 and Smad6 binds to a BMP2 downstream kinase TAK1.
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