Control of Linker Cell Death in C. elegans

线虫中连接细胞死亡的控制

基本信息

批准号：
9209966
负责人：
Shai Shaham
金额：
$ 35.17万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
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/9209966
关键词：
Adult Animals Apoptosis Apoptotic Artificial Insemination Autophagocytosis BCL2 gene BH3 Domain CASP3 gene CASP9 gene Caenorhabditis elegans Caspase Cell Death Cell Death Process Cell Survival Cells Cessation of life Chromatin Critical Pathways Cues Defect Development Disease ENG gene Electron Microscope Employee Strikes Endoplasmic Reticulum Family Genes Genetic Screening Genetic study 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 Physical shape Play Prevalence Process Proteins RNA interference screen Regulation Regulator Genes Role Sterility Structure Swelling Testing Tissues Transcript WNT Signaling Pathway apoptotic protease-activating factor 1 genome-wide human disease killings male mutant novel polyglutamine programs promoter public health relevance transcriptome

项目摘要

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型非凋亡性发育细胞死亡程序，及其与聚谷氨酰胺诱导的神经退行性疾病的关系。细胞死亡是后生动物发育过程中的主要细胞命运。细胞凋亡是一种广泛研究的细胞死亡过程，需要半胱天冬酶蛋白酶，并伴有典型的形态学特征。令人惊讶的是，缺乏凋亡效应子的小鼠能够存活到成年，这提高了非凋亡细胞死亡可能在动物发育中发挥关键作用的可能性。因此，一个未解决的主要问题是是否存在替代的发育细胞死亡途径，如果存在，什么分子机制控制其执行。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。相反，垂死的 LC 显示出明显的核膜凹陷（锯齿形）、未浓缩的染色质以及内质网和线粒体的肿胀。重要的是，LC 死亡独立于 CED-3 caspase、所有其他 caspase 以及所有其他已知的线虫凋亡蛋白，包括 CED-4/Apaf-1、CED-9/Bcl-2 家族以及 EGL-1 和 CED -13 个仅包含 BH3 结构域的蛋白质。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。通过全基因组 RNAi 筛选促进 LC 死亡的基因，我们鉴定了 LC 死亡所需的几个基因，其中包括编码富含谷氨酰胺的蛋白质的基因。 LC死亡在超微结构上与脊椎动物神经系统中的非凋亡性发育细胞死亡具有惊人的相似性，并且一些观察结果也表明与多聚谷氨酰胺诱导的神经变性有相似之处。在此，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的功能； (2) 表征从遗传筛选中鉴定出的新 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了解人类发育和疾病中的细胞死亡过程。