Control of Linker Cell Death in C. elegans

线虫中连接细胞死亡的控制

• 批准号: 8976786
• 负责人: Shai Shaham
• 金额: $ 34.82万
• 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/8976786
• 关键词: Adult; Affect; Animals; Apoptosis; Apoptotic; Artificial Insemination; Autophagocytosis; BCL2 gene; BH3 Domain; CASP3 gene; 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; Genes; Genetic Screening; Genetic study; Glutamine; Goals; Health; 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; Physical shape; Play; Prevalence; Process; Proteins; RNA interference screen; Regulation; Regulator Genes; Role; Signal Pathway; Signal Transduction; Sterility; Structure; Swelling; Testing; Tissues; Transcript; apoptotic protease-activating factor 1; base; genome-wide; human disease; killings; male; mutant; novel; polyglutamine; promoter; transcriptome

DESCRIPTION (provided by applicant): 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 vertebrate's cell death, our results may contribute towards an understanding of cell death processes in human development and disease.

描述(由申请人提供)：我们的长期目标是了解我们发现的一种新的非凋亡性发育细胞死亡计划，以及它与聚谷氨酰胺诱导的神经退行性疾病的关系。细胞死亡是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，需要半胱氨酸天冬氨酸蛋白酶，并伴随着典型的形态特征。令人惊讶的是，缺乏凋亡效应的小鼠可以存活到成年，这增加了非凋亡性细胞死亡可能在动物发育中发挥关键作用的可能性。因此，一个尚未解决的主要问题是，是否存在可供选择的发育细胞死亡途径，如果存在，控制其执行的分子机制是什么。我们最近发现，线虫雄性特异性连接细胞(LC)的死亡不是凋亡的。相反，垂死的LC显示出明显的核膜凹陷(皱缩)、未浓缩的染色质以及内质网和线粒体的肿胀。重要的是，LC死亡不依赖于CED-3 caspase、所有其他caspase和所有其他已知的线虫凋亡蛋白，包括CED-4/APAF-1、CED-9/Bcl-2家族、EGL-1和CED-13 BH3结构域蛋白。这些令人兴奋的发现表明，LC死亡必须通过一种新的机制发生。从全基因组RNAi筛选促进LC死亡的基因中，我们确定了LC死亡所需的几个基因，包括一个编码富含谷氨酸的蛋白质的基因。LC死亡表现出与脊椎动物神经系统中非凋亡性发育细胞死亡的惊人的超微结构相似之处，一些观察也表明类似于多聚谷氨酰胺诱导的神经退化。在这里，我们建议(1)研究PQN-41的功能并确定相互作用蛋白的功能；(2)从遗传筛选中鉴定新的LC死亡基因；(3)了解LC死亡的控制。鉴于LC死亡和脊椎动物细胞死亡之间的相似性，我们的结果可能有助于理解人类发育和疾病中的细胞死亡过程。