|Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
gp130 is a signal-transducing receptor component used in common by the interleukin-6 (IL-6) family of cytokines, including IL-6, IL-11, leukemia inhibitory factor (LIF) ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and cardiotrophin-1 (CT-1). When we started this project, neurotrophic role of gp130 in the nervous system had been suggested, although direct evidence indicating the importance of gp130 in the developmental and maintenance of the nervous system in vivo had not been obtained. Firstly, we have clarified in this study that gp130 supports survival of newly generated sensory and motor neurons during the late phase of development when naturally occurring cell death takes place. Secondary, We have found that LIF and bone morphogenetic protein (BMP2), which signal through distinct signaling pathways, act in synergy on cultured fetal neural progenitor cells to induce astrocytes. We have further demonstrated that respective downstream transcription factors, STAT3 and Smads, form a complex bridged by a transcriptional coactivator p300, which may explain cooperative induction of astrocytes by LIF and BMP2 from neural progenitors. Thirdly, we have shown that brief exposure to BMP2 was sufficient to change the fate of telencephalic neural progenitors in culture, from neuronal to astrocytic. BMP2 upregulated expression of negative helix-loop-helix (HLH) factors, Id1, Id3 and Hes-5, which all actually inhibited transcriptional activity of neurogenic HLH transcription factors, Mash1 and Neurogenin. Ectopic expression of either Id1 or Id3 inhibited neurogenesis from neuroepithelial cells, suggesting an important role of these negative HLH proteins in BMP2-mediated alteration of neurogenic fate of these cells.