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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：
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
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/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

项目摘要

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发育性细胞死亡程序