Programmed cell death is an essential process during metazoan development. During development of the nematode C. elegans nearly all cells slated to die activate caspases and undergo stereotypical morphological changes, including chromatin compaction and cell shrinkage. The male-specific linker cell, however, is an exception. The linker cell leads the migration of the developing gonad and once migration is complete the cell dies. Strikingly, mutations in the genes ced-3/caspase, ced-4/Apaf-1, egl-1/BH3-only, or ced-9/BCL2, the main regulators of apoptosis in C. elegans, do not affect linker cell death. Linker cell death must, therefore, be controlled by a novel program. Electron micrographs of dying linker cells reveal nonapoptotic features, including nuclear membrane invaginations, absence of chromatin condensation, and swelling of mitochondria and the endoplasmic reticulum. Similar features are seen in dying vertebrate neurons during development and in neurons that die from polyglutamine-induced toxicity as occurs in Huntington's disease and other spinocerebellar ataxias.

To understand the molecular basis of linker cell death we sought genes that regulate the process. We have identified over 15 genes controlling linker cell demise and have begun to place these in genetic pathways. Our results demonstrate that linker cell death is initiated by a cell-autonomous transcriptional program that induces the expression of genes required to promote linker cell death. One transcriptional target, the gene pqn-41, has been studied in detail. pqn-41 encodes a 2100 amino-acid protein with a C-terminal domain in which 151 of 427 amino acids are glutamine. pqn-41 expression is induced in the linker cell just prior to onset of death, and the protein partitions to both nucleus and cytoplasm, accumulating in cytoplasmic puncta. Importantly, an endogenous transcript encoding only the polyglutamine domain of pqn-41 is sufficient to rescue pqn-41 mutants. pqn-41 functions together with a MAPK pathway and a pathway regulated by the microRNA let-7, whose expression is often disrupted in human lung cancer.

Our results demonstrate the existence of a new metazoan cell death pathway and raise the possibility that neurodegenerative diseases resulting from polyglutamine expansions may inappropriately activate this program to cause neuronal loss.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY09-02. doi:10.1158/1538-7445.AM2011-SY09-02