LIN-3/EGF promotes the programmed cell death of specific cells in Caenorhabditis elegans by transcriptional activation of the pro-apoptotic gene egl-1.
PLoS Genet 2014;
10:e1004513. [PMID:
25144461 PMCID:
PMC4140636 DOI:
10.1371/journal.pgen.1004513]
[Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 06/05/2014] [Indexed: 12/13/2022] Open
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.
Programmed cell death (PCD) is an evolutionarily conserved cellular process that is important for metazoan development and homeostasis. The epidermal growth factor (EGF) promotes cell proliferation, differentiation and survival during animal development. Surprisingly, we found that the EGF-like ligand LIN-3 also promotes the death of specific cells in Caenorhabditis elegans. We found that the LIN-3/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. To our knowledge, LIN-3/EGF is the first extrinsic signal that has been shown to regulate the intrinsic PCD machinery during C. elegans development. In addition, the transcription factor LIN-31, which binds to LIN-1 and acts downstream of LIN-3/EGF, LET-23/EGF receptor, and the MAPK signaling pathway during vulval development, is dispensable for PCD. Thus, LIN-3/EGF promotes cell proliferation, differentiation, and PCD through common downstream signaling molecules but acts via distinct sets of transcription factors for different target gene expression.
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