Transcriptional control of non-apoptotic developmental cell death in C. elegans

Abstract

Programmed cell death is an essential aspect of animal development. Mutations in vertebrate genes that mediate apoptosis only mildly perturb development, suggesting that other cell death modes likely have important roles. Linker cell-type death (LCD) is a morphologically conserved cell death form operating during the development of Caenorhabditis elegans and vertebrates. We recently described a molecular network governing LCD in C. elegans, delineating a key role for the transcription factor heat-shock factor 1 (HSF-1). Although HSF-1 functions to protect cells from stress in many settings by inducing expression of protein folding chaperones, it promotes LCD by inducing expression of the conserved E2 ubiquitin-conjugating enzyme LET-70/UBE2D2, which is not induced by stress. Following whole-genome RNA interference and candidate gene screens, we identified and characterized four conserved regulators required for LCD. Here we show that two of these, NOB-1/Hox and EOR-1/PLZF, act upstream of HSF-1, in the context of Wnt signaling. A third protein, NHR-67/TLX/NR2E1, also functions upstream of HSF-1, and has a separate activity that prevents precocious expression of HSF-1 transcriptional targets. We demonstrate that the SET-16/mixed lineage leukemia 3/4 (MLL3/4) chromatin regulation complex functions at the same step or downstream of HSF-1 to control LET-70/UBE2D2 expression. Our results identify conserved proteins governing LCD, and demonstrate that transcriptional regulators influence this process at multiple levels.

Non-apoptotic cell death in animal development

“…61 Two transcription factors, NOB-1/Hox and the EOR-1/-2/PLZF complex, likely control the EGL-20/Wnt pathway. 62 In parallel, TIR-1, the C. elegans ortholog of mammalian Sarm, activates the MAPKK protein SEK-1 to promote death. 63 SEK-1 may promote expression of the polyglutamine-repeat protein PQN-41.…”

“…63 The zinc-finger protein LIN-29, a component of a developmental timing program, 64 also promotes death, as does the nuclear hormone receptor NHR-67. 62 These genes appear to act independently of and in parallel to the Wnt and MAPKK pathways. 62 Linker cell death can be restored in mutants carrying lesions in the upstream control pathways by a gain-of-function mutation in HSF-1, a highly conserved transcriptional regulator of the heat shock and other stress responses.…”

“…62 These genes appear to act independently of and in parallel to the Wnt and MAPKK pathways. 62 Linker cell death can be restored in mutants carrying lesions in the upstream control pathways by a gain-of-function mutation in HSF-1, a highly conserved transcriptional regulator of the heat shock and other stress responses. HSF-1 loss-of-function blocks death.…”

“…61 Genetically, HSF-1 functions at the same step as the SET-16/MLL3/4 H3K4 histone methyltransferase complex. 62 Genetic, expression and functional studies suggest that HSF-1 may work by transcriptionally activating components of the ubiquitin proteasome system. 61 The single C. elegans E1 enzyme, UBA-1, is required through activity of the E2 ubiquitin-conjugating enzyme LET-70, homologous to mammalian UBE2D2.…”

RAB-35 and ARF-6 GTPases Mediate Engulfment and Clearance Following Linker Cell-Type Death

“…LET-70/UBE2D2, together with other components of the ubiquitin proteasome system, then drive LCD and linker cell clearance [20][21][22] . Following LCD initiation, the linker cell is engulfed 23 .…”