Abstract
Programmed cell death (PCD) is the physiological death of a cell mediated by an intracellular suicide program. Although key components of the PCD execution pathway have been identified, how PCD is regulated during development is poorly understood. Here, we report that the epidermal growth factor (EGF)-like ligand LIN-3 acts as an extrinsic signal to promote the death of specific cells in Caenorhabditis elegans. The loss of LIN-3 or its receptor, LET-23, reduced the death of these cells, while excess LIN-3 or LET-23 signaling resulted in an increase in cell deaths. Our molecular and genetic data support the model that the LIN-3 signal is transduced through LET-23 to activate the LET-60/RAS-MPK-1/ERK MAPK pathway and the downstream ETS domain-containing transcription factor LIN-1. LIN-1 binds to, and activates transcription of, the key pro-apoptotic gene egl-1, which leads to the death of specific cells. Our results provide the first evidence that EGF induces PCD at the whole organism level and reveal the molecular basis for the death-promoting function of LIN-3/EGF. In addition, the level of LIN-3/EGF signaling is important for the precise fine-tuning of the life-versus-death fate. Our data and the previous cell culture studies that say EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans.
Highlights
Programmed cell death (PCD) is important for proper animal development and tissue homeostasis [1,2] and its dysregulation can cause aberrant death or survival of cells, which may lead to developmental defects, degenerative diseases, or cancers [1,2].Caenorhabditis elegans is an excellent model for studying PCD because of its invariant cell lineage and the conserved cell death pathway [3,4]
We found that the LIN-3/epidermal growth factor (EGF) signal can be secreted from a cell to facilitate the demise of cells at a distance by activating the transcription of the PCD-promoting gene egl-1 in the doomed cells through the transcription factor LIN-1
LIN-1 binds to the egl-1 promoter in vitro and is positively regulated by the LIN-3/EGF, LET-23/EGF receptor, and the downstream MAPK signaling pathway
Summary
PCD is important for proper animal development and tissue homeostasis [1,2] and its dysregulation can cause aberrant death or survival of cells, which may lead to developmental defects, degenerative diseases, or cancers [1,2].Caenorhabditis elegans is an excellent model for studying PCD because of its invariant cell lineage and the conserved cell death pathway [3,4]. Several transcription factors controlling egl-1 transcription have been identified and shown to specify the PCD fate of specific cells [4,18]. Two transcription factors HLH-2 and HLH-3 activate egl-1 transcription by direct binding to the egl-1 cis-regulatory region during the specification of the death fate of NSM sister cells [18,19]. Like HLH-2 and HLH-3, cell death specification genes have been shown to transcriptionally regulate the components of the core PCD machinery in a cell-autonomous manner. It is unclear whether the PCD fate, like many other cell fates, may be regulated by an extrinsic signal
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