京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22350号 / 医博第4591号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 斎藤 通紀, 教授 浅野 雅秀, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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<p dir="ltr">Delta-like 1 (DLL1) is a protein on the surface of the cell that serves as a ligand for NOTCH receptors. Like NOTCH receptors, NOTCH ligands span the membrane of the cell and contain extracellular, transmembrane, and intracellular domains. NOTCH activation occurs through contact-dependent interactions between the NOTCH receptor on one cell and ligand on an adjacent cell. Previous studies have demonstrated that DLL1 predominantly functions cell non-autonomously to trigger NOTCH signaling in a neighbor cell but a cell-autonomous function of DLL1 has also been proposed in recent years. However, there is no direct evidence to support a cell-autonomous function of DLL1 in vivo. The overall goal of this thesis was to elucidate the cell-autonomous function of DLL1 by testing the hypothesis that the intracellular domain of DLL1 (DLL1ICD) can be cleaved and function in the DLL1-expressing cell in addition to triggering NOTCH signaling in a neighbor cell. The research strategy to test the hypothesis is by overexpression of full-length (FL) and cleaved Dll1 (Dll1ICD) in the murine myoblast cell line (C2C12). These plasmids utilize a tet-on system for inducible overexpression. Transfected myoblasts were used to analyze how overexpression of Dll1-FL and Dll1ICD affects proliferation, differentiation, fusion, and gene expression. The results show that Dll1-FL can be cleaved to generate an ICD. DLL1ICD overexpression promotes fusion without affecting proliferation. Further investigation reveals that overexpression of Dll1ICD affects the expression of NOTCH and myogenic-specific genes during differentiation, confirming the cell-autonomous role of DLL1ICD in myoblasts. These results together show that DLL1 can function cell autonomously through its intracellular domain to regulate myogenesis.</p>