Control of nonapoptotic C. elegans cell death similar to neurodegeneration

点击翻译按钮获取中文摘要

Our long-term goal is to understand the molecular basis of a novel morphologically-conserved non-apoptotic developmental cell-death program we uncovered, and to determine its roles in mammalian development and disease. Programmed cell death is a major cell fate. Apoptosis, an extensively studied cell death process, requires caspase proteases and is accompanied by chromatin compaction and cytoplasmic shrinkage. Surprisingly, mice lacking apoptotic effectors survive to adulthood. These observations suggest that non- apoptotic cell death may play key roles in animal development. Although genes promoting necrotic cell death have been described, these are not required for development. Thus, whether alternative developmental cell death pathways exist, and if so, what molecular mechanisms govern their execution, is a major outstanding question. Our studies of the C. elegans linker cell provide direct evidence that caspase-independent non- apoptotic cell death pathways operate during animal development. Linker cell death occurs in the absence of C. elegans caspases, and other apoptosis genes are also not required, nor are genes implicated in autophagy or necrosis. The morphology of a dying linker cell is characterized by lack of chromatin condensation, a crenellated nucleus, and swelling of cytoplasmic organelles. Remarkably, cell death with similar features (linker cell-type death, LCD) also occurs in vertebrates, and is characteristic of neuronal degeneration in polyglutamine diseases. We recently described a pathway governing C. elegans LCD. This is the first such framework for a non-apoptotic developmental cell-death program. LCD is controlled by Wnt signals that function in parallel with a developmental-timing and a MAPKK pathway to control non-canonical activity of HSF-1, a conserved heat-shock transcription factor. let-70/Ube2D2, encoding a conserved E2 ubiquitin- conjugating enzyme, is a key target of HSF-1. The E3 components CUL-3/cullin, RBX-1, and BTBD-2 function with LET-70/UBE2D2 for LCD. LCD pathway components are involved in vertebrate cell-degenerative processes. pqn-41, encoding a self-aggregating glutamine-rich protein, is reminiscent of polyglutamine repeat proteins causing neurodegeneration. tir-1/Sarm as well as the E3 component BTBD-2, promote distal axon degeneration following axotomy in mice, supporting conserved cell dismantling roles. Here we will build on these studies to uncover LCD pathway targets, and study relevance to mammalian development. We will: (1) Investigate how HSF-1 function in LCD differs from its heat-shock response roles. (2) Identify BTBD-2 target genes and assess roles in LCD control. (3) Use our knowledge of the LCD mechanism to investigate its conservation during Müllerian duct degeneration and early embryonic development in the mouse, where cell death is non-apoptotic and morphologically similar to LCD. Our results may contribute to an understanding of cell death processes in human development and disease.