Molecular Genetic Characterization of Mutationally-Induced Cell Death in C. Elegans

两个C.线虫基因mec-4和deg-1诱导 特定神经元群的死亡。垂死的神经元 特征是细胞肿胀，形态学上类似于 常见的死亡模式称为坏死。 因为在C. 线虫的细胞死亡机制可以用遗传学方法来分析， 这种坏死样死亡的表征方法应该 提供了对死亡过程的新见解 MEC-4和DEG-1是 似乎编码膜蛋白的基因家族的成员。 这些基因（称为退化基因）以相同的方式突变， 导致死亡。 mec-4和deg-1 DNA序列似乎交叉 与许多物种的DNA杂交， 其他基因组中的基因简并蛋白家族成员 生物体也有可能发生突变， 死亡 这项研究的长期目标是确定 MEC-4（d）诱导的细胞死亡发生在分子水平， 研究是否在其他疾病中使用了类似的死亡机制 细胞类型和其他生物。 具体而言，工作概述 在本提案中，将1）完成结构/功能分析 为了确定MEC-4功能所需的结构域和氨基酸，2） 鉴定阻断mec-4（d）诱导死亡的抑制突变， 鉴定参与死亡过程的蛋白质，以及3） 分离来自不同物种退化蛋白家族成员。 %%% 阐明细胞死亡的机制对于 了解发育、体内平衡和病理学。

Dominant mutations in two C. elegans genes, mec-4 and deg-1, induce the deaths of specific groups of neurons. Dying neurons are characterized by cell swelling and morphologically resemble a commonly observed pattern of death termed necrosis. Because in C. elegans cell death mechanisms can be dissected using genetic approaches characterization of this necrotic like death should provide novel insight into this death process. Mec-4 and deg-1 are members of a gene family that appear to encode membrane proteins. These genes (called degenerin genes) mutate in the same way to induce death. mec-4 and deg-1 DNA sequences appear to cross hybridize to DNAs from a number of species, raising the possibility that members of gene degenerin families in other organisms might also be capable of mutation to forms that induce death. The term long objective of the research is to determine how mec-4 (d) induced cell death occurs at the molecular level and to investigate whether similar death mechanisms are utilized in other cell types and in other organisms. Specifically, the work outlined in this proposal will 1) accomplish a structure/function analysis to define domains and amino acids required for mec-4 function, 2) identify suppressor mutations that block mec-4(d)-induced death to identify proteins that participate in the death process, and 3) isolate degenerin family members from different species. %%% Elucidation of mechanisms of cell death are important for understanding development, homeostasis and pathology.