| Co-Investigator(Kenkyū-buntansha) |
KITAMURA Hitoshi Yokohama City University, School of Medicine, Professor, 医学部, 教授 (20094302)
KAGEYAMA Ryoichiro Kyoto University, Virus Institute, Professor, ウイルス研究所, 教授 (80224369)
宇高 直子 横浜市立大学, 医学部, 助手 (90285106)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
In the present study, we investigated the significance of pronueral basic helix-loop-helix transcription factors for the differentiation of pulmonary neuroendocrine cells (PNEC) using the mutant mice difcient of the genes of mammalian homolog of achaete scute complex (Mash1) and hairy and Enhancer of split (Hes1), and evaluated involvement of Notch signalling system in the determiantion of pulmonary epithelial cell differentiation.
Immunohistochemical studies revealed that PNEC were positive for Mash1, but not for Hes1. In the contrary, non-neuroendocrine cells (NPNEC) were negative for Mash1, but positive for Hes1. In the mouse lungs from Mash1 null mice, PNEC were not detected, while in the mice lungs from Hes1 null mice, hyperplasia of PNEC was observed. When primary epithelial culture cells obtained from mouse fetal lungs were trasfected with Mash1 gene, cells with neuroendocrine phenotypes were induced. Moreover, immunohistochemical studies revealed that PNEC were positive for Delta-like 1 (Dll1), a Notch ligand, but not for Notch receptors and ligands (Jagged1 and Jagged2). In the contrary, NPNEC were negative for Dll1, but positive for Notch1-3, Jagged1 and Jagged2. In the mouse lungs from Mash1 null mice, Dll1 mRNA was not detected, while in the mice lungs from Hes1 null mice, expression of Notch1 and Jagged1 mRNAs was reduced.
Thus, differentiation of mouse airway epithelial cells is regulated by a network of basic helix-loop-helix factors, and Notch signalling pathway could work in the cell fate determination of lung epithelial cells.
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