Genetitc control of programmed cell death in central nervous system

中枢神经系统程序性细胞死亡的遗传控制

• 批准号: 13480257
• 负责人: MIURA Masayuki
• 金额: $ 9.22万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13480257/
• 关键词: Drosophila; neuron; genetics; cell death; screening

To discover the cell death triggers encoded in the Drosophila genome, we conducted a misexpression screen using the GAL4/UAS system. The GS vector is a P element-based gene search vector with UAS enhancers (Toba et al., 1999). We crossed a collection of 5,000 lines harboring the GS vector (GS lines) with an eye-specific GAL4 (GMR-GAL4) strain to screen for genes that generated the reduced-eye phenotype. In our large-scale gain-of-function screen, we identified Eiger, the first invertebrate tumor necrosis factor (TNF) superfamily ligand that can induce cell death. Eiger is a type II transmembrane protein with a C-terminal TNF nomology domain. It is predominantly expressed in the nervous system. Genetic evidence shows that Eiger induces cell death by activating the Drosophila JNK pathway. Although this cell death process is blocked by Drosophila inhibitor-of-apoptosis protein 1 (D1AP1), it does not require caspase activity. We also show genetically that Eiger is a physiological ligand for the Drosophila JNK pathway. Our findings demonstrate that Eiger can initiate cell death through an IAP-sensitive cell-death pathway via JNK signaling.

为了发现果蝇基因组中编码的细胞死亡触发因子，我们使用GAL4/UAS系统进行了错误表达筛选。GS载体是具有UAS增强子的基于P元件的基因搜索载体（Toba等人，1999年）。我们将含有GS载体的5，000个株系（GS株系）与眼特异性GAL4（GMR-GAL4）株系杂交，以筛选产生减少眼表型的基因。在我们的大规模功能获得性筛选中，我们鉴定了Eiger，这是第一个可以诱导细胞死亡的无脊椎动物肿瘤坏死因子（TNF）超家族配体。Eiger是一种II型跨膜蛋白，具有C-末端TNF法则结构域。它主要在神经系统中表达。遗传学证据表明，Eiger通过激活果蝇JNK途径诱导细胞死亡。虽然这种细胞死亡过程被果蝇凋亡通道蛋白1（D1AP 1）阻断，但它不需要半胱天冬酶活性。我们还表明，Eiger基因是果蝇JNK途径的生理配体。我们的研究结果表明，Eiger可以启动细胞死亡，通过IAP敏感的细胞死亡途径，通过JNK信号。

项目成果

Igaki, T., Yamamoto-Goto, Y.,Tokushige, N., Kanda, H., Miura, M.: "Downregulation of DIAP1 triggers a novel Drosophila cell death pathway mediated by DARK and DRONC"J. Biol. Chem.. 277. 23103-23106 (2002)

Igaki, T.、Yamamoto-Goto, Y.、Tokushige, N.、Kanda, H.、Miura, M.：“DIAP1 的下调触发由 DARK 和 DRONC 介导的新型果蝇细胞死亡途径”J.

Hisahara, S., Yuan, J., Momoi, T., Okano, H., Miura, M.: "Caspase-11 mediates oligodendrocytes cell death and pathogenesis of autoimmune-mediated demyelination"J. Exp. Med.. 193. 111-122 (2001)

Hisahara, S.、Yuan, J.、Momoi, T.、Okano, H.、Miura, M.：“Caspase-11 介导少突胶质细胞死亡和自身免疫介导的脱髓鞘的发病机制”J.

Kim, K.W., Chung, H.H., Chung, C.W.et al.: "Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3 : Cleavage of the common alpha subunit during apoptosis"Oncogene. 20. 358-366 (2001)

Kim, K.W.、Chung, H.H.、Chung, C.W.等人：“caspase-3 对法尼基转移酶和香叶基香叶基转移酶 I 的灭活：细胞凋亡过程中常见 α 亚基的裂解”癌基因。

Igaki, T., Kanda, H., Yamamoto-Goto, Y., Kanuka, H., Kuranaga, E., Aigaki, T., Miura, M.: "Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway"EMBO J.. 21. 3009-3018 (2002)

Igaki, T.、Kanda, H.、Yamamoto-Goto, Y.、Kanuka, H.、Kuranaga, E.、Aigaki, T.、Miura, M.：“Eiger，一种触发果蝇 JNK 通路的 TNF 超家族配体

Kuranaga, E., Kanuka, H., Igaki, T., Sawamoto, K., Ichijo, H., Okano, H., and Miura, M.: "Reaper-mediated inhibition of DIAP1-induced Drosophila TRAF1 degradation leads to JNK activation"Nature Cell Biol.. 4. 705-710 (2002)

Kuranaga, E.、Kanuka, H.、Igaki, T.、Sawamoto, K.、Ichijo, H.、Okano, H. 和 Miura, M.：“Reaper 介导的 DIAP1 诱导的果蝇 TRAF1 降解抑制导致