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.

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Our long-term goal is to understand how cell death takes place during normal animal development and disease. We recently uncovered a novel cell death process in the nematode C. elegans with similarities to normal and disease-related cell death in humans. Here we aim to understand the details of this novel killing mechanism, and how it becomes activated during normal development. Our studies may, therefore, describe general principles for cell death control in normal development and perhaps in disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Mukhopadhyay, Mahua
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Rockefeller University
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New York
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Ghose, Piya; Rashid, Alina; Insley, Peter et al. (2018) EFF-1 fusogen promotes phagosome sealing during cell process clearance in Caenorhabditis elegans. Nat Cell Biol 20:393-399
Kutscher, Lena M; Keil, Wolfgang; Shaham, Shai (2018) RAB-35 and ARF-6 GTPases Mediate Engulfment and Clearance Following Linker Cell-Type Death. Dev Cell 47:222-238.e6
Keil, Wolfgang; Kutscher, Lena M; Shaham, Shai et al. (2017) Long-Term High-Resolution Imaging of Developing C. elegans Larvae with Microfluidics. Dev Cell 40:202-214
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