Control of Linker Cell Death in C. elegans

线虫中连接细胞死亡的控制

• 批准号: 8621260
• 负责人: Shai Shaham
• 金额: $ 35.17万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621260
• 关键词: Adult; Affect; Animals; Apoptosis; Apoptotic; Artificial Insemination; Autophagocytosis; BCL2 gene; BH3 Domain; Caenorhabditis elegans; Caspase; Cell Death; Cell Death Process; Cell Survival; Cells; Cessation of life; Chromatin; Cues; Defect; Development; Disease; Electron Microscope; Employee Strikes; Endoplasmic Reticulum; Family; Gene Expression Profile; Genes; Genetic; Genetic Screening; Glutamine; Goals; Hour; Human; Human Development; Hybrids; Lesion; Mediating; Mitochondria; Molecular; Molecular Genetics; Morphology; Mus; Mutation; Necrosis; Nematoda; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Nuclear; Nuclear Envelope; Organelles; Pathway interactions; Peptide Hydrolases; Phenotype; Play; Prevalence; Process; Proteins; RNA Interference; Regulation; Regulator Genes; Role; Signal Pathway; Signal Transduction; Sterility; Structure; Swelling; Testing; Tissues; Transcript; apoptotic protease-activating factor 1; base; caspase-3; genome-wide; human disease; killings; male; mutant; novel; polyglutamine; promoter; public health relevance

Our long-term goal is to understand a novel nonapoptotic developmental cell death program we discovered, and its relationship to polyglutamine-induced neurodegenerative disease. Cell death is a major cell fate during metazoan development. Apoptosis, an extensively studied cell death process, requires caspase proteases and is accompanied by a stereotypical morphological signature. Surprisingly, mice lacking apoptotic effectors survive to adulthood, raising the possibility that non- apoptotic cell death may play key roles in animal development. Thus, a major unsolved question is whether alternative developmental cell death pathways exist, and if so, what molecular mechanisms govern their execution. We recently discovered that the death of the C. elegans male-specific linker cell (LC) is not apoptotic. Instead, the dying LC displays pronounced indentation (crenellation) of the nuclear envelope, uncondensed chromatin, and swelling of the endoplasmic reticulum and mitochondria. Importantly, LC death is independent of CED-3 caspase, all other caspases, and all other known C. elegans apoptotic proteins, including CED-4/Apaf-1, CED-9/Bcl-2 family, and EGL-1 and CED-13 BH3-domain-only proteins. These exciting findings demonstrate that LC death must occur through a novel mechanism. From a genome-wide RNAi screen for genes promoting LC death we identified several genes required for LC death, including one encoding a protein rich in glutamines. LC death displays striking ultrastructural similarities to nonapoptotic developmental cell death in the vertebrate nervous system and several observations also suggest similarities to polyglutamine-induced neurodegeneration. Here we propose to (1) to study aspects of PQN-41 function and determine functions of interacting proteins; (2) characterize new LC death genes identified from a genetic screen; and (3) understand the control of LC death. Given the similarities between LC death and vertebrates cell death, our results may contribute towards an understanding of cell death processes in human development and disease.

我们的长期目标是了解一种新的非凋亡性发育细胞死亡程序， 发现，及其与聚谷氨酰胺诱导的神经退行性疾病的关系。细胞死亡是一种 在后生动物发育过程中的主要细胞命运。细胞凋亡是一种被广泛研究的细胞死亡过程， 需要半胱天冬酶蛋白酶，并伴随着定型的形态学特征。 令人惊讶的是，缺乏凋亡效应物的小鼠可以存活到成年，这增加了非凋亡效应物的可能性。 凋亡性细胞死亡可能在动物发育中起关键作用。因此，一个尚未解决的主要问题是， 是否存在替代性发育细胞死亡途径，如果存在，分子机制是什么 管理他们的执行。我们最近发现C.线虫雄性特异性接头 细胞（LC）不凋亡。相反，垂死的LC显示出明显的凹陷（锯齿状）， 核被膜、染色质未凝聚和内质网肿胀， 线粒体重要的是，LC死亡独立于CED-3半胱天冬酶、所有其他半胱天冬酶和所有其他半胱天冬酶。 已知C。线虫凋亡蛋白，包括CED-4/Apaf-1、CED-9/Bcl-2家族和EGL-1， CED-13仅BH 3结构域蛋白。这些令人兴奋的发现表明，LC死亡必须发生 通过一种新的机制。通过全基因组RNAi筛选促进LC死亡的基因， 确定了LC死亡所需的几个基因，包括一个编码富含谷氨酰胺的蛋白质。LC 死亡显示出惊人的超微结构相似的非凋亡性发育细胞死亡， 脊椎动物神经系统和一些观察结果也表明类似于聚谷氨酰胺诱导的 神经变性在这里，我们建议（1）研究PQN-41功能的各个方面，并确定 相互作用蛋白质的功能;（2）表征从遗传筛选中鉴定的新LC死亡基因; 了解LC死亡的控制。鉴于LC死亡和脊椎动物之间的相似性 细胞死亡，我们的研究结果可能有助于对人类细胞死亡过程的理解 发展和疾病。