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Transcriptional upregulation of both egl-1 BH3-only and ced-3 caspase is required for the death of the male-specific CEM neurons.

Nehme R, Grote P, Tomasi T, Löser S, Holzkamp H, Schnabel R, Conradt B - Cell Death Differ. (2010)

Bottom Line: We found that in the CEMs, the transcriptional activation of both the egl-1 and ced-3 gene is necessary for apoptosis induction.Furthermore, we identified three genes, unc-86, lrs-1, and unc-132, which encode a POU homeodomain transcription factor, a leucyl-tRNA synthetase, and a novel protein with limited sequence similarity to the mammalian proto-oncoprotein and kinase PIM-1, respectively, that promote the expression of the ceh-30 gene in the CEMs. On the basis of these results, we propose that egl-1 and ced-3 transcription are coregulated in the CEMs to compensate for limiting proCED-3 levels, which most probably are a result of proCED-3 turn over.Finally, we present evidence that the timing of the death of the CEMs is controlled by TRA-1 Gli, the terminal global regulator of somatic sexual fate in C. elegans.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Dartmouth Medical School, Norris Cotton Cancer Center, Hanover, NH 3755, USA.

ABSTRACT
Most of the 131 cells that die during the development of a Caenorhabditis elegans hermaphrodite do so approximately 30 min after being generated. Furthermore, in these cells, the pro-caspase proCED-3 is inherited from progenitors and the transcriptional upregulation of the BH3-only gene egl-1 is thought to be sufficient for apoptosis induction. In contrast, the four CEM neurons, which die in hermaphrodites, but not males, die approximately 150 min after being generated. We found that in the CEMs, the transcriptional activation of both the egl-1 and ced-3 gene is necessary for apoptosis induction. In addition, we show that the Bar homeodomain transcription factor CEH-30 represses egl-1 and ced-3 transcription in the CEMs, thereby permitting their survival. Furthermore, we identified three genes, unc-86, lrs-1, and unc-132, which encode a POU homeodomain transcription factor, a leucyl-tRNA synthetase, and a novel protein with limited sequence similarity to the mammalian proto-oncoprotein and kinase PIM-1, respectively, that promote the expression of the ceh-30 gene in the CEMs. On the basis of these results, we propose that egl-1 and ced-3 transcription are coregulated in the CEMs to compensate for limiting proCED-3 levels, which most probably are a result of proCED-3 turn over. Similar coregulatory mechanisms for BH3-only proteins and pro-caspases may function in higher organisms to allow efficient apoptosis induction. Finally, we present evidence that the timing of the death of the CEMs is controlled by TRA-1 Gli, the terminal global regulator of somatic sexual fate in C. elegans.

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Model of the life-versus-death decision in the CEMsTop panel. Most cells programmed to die do so ~30 min after being generated. In these cells, proCED-3 protein inherited from the progenitor is sufficient for apoptosis induction in response to egl-1 transcriptional activation. Bottom panel. The CEMs in hermaphrodites die ~150 min after being generated (~470 min after the first cell division). Increasing TRA-1 activity results in decreasing CEH-30 activity, which is required for the de-repression of egl-1 and ced-3 transcription. The activation at the transcriptional level of the ced-3 gene compensates for decreased levels of proCED-3. See text for details.
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Figure 7: Model of the life-versus-death decision in the CEMsTop panel. Most cells programmed to die do so ~30 min after being generated. In these cells, proCED-3 protein inherited from the progenitor is sufficient for apoptosis induction in response to egl-1 transcriptional activation. Bottom panel. The CEMs in hermaphrodites die ~150 min after being generated (~470 min after the first cell division). Increasing TRA-1 activity results in decreasing CEH-30 activity, which is required for the de-repression of egl-1 and ced-3 transcription. The activation at the transcriptional level of the ced-3 gene compensates for decreased levels of proCED-3. See text for details.

Mentions: One obvious question that arises from our studies is why CEMs survive for ~150 rather than ~30 min before they undergo apoptosis. The CEMs are born ~320 min after the first cell division and die in hermaphrodites at ~470 min (12). The TRA-1 protein plays a pivotal role in the life-versus-death decision of the CEMs. In the CEMs, TRA-1 represses ceh-30 transcription thereby causing egl-1 and ced-3 de-repression and apoptosis induction. The activity of TRA-1 is regulated at the post-translational level by sex-specific cleavage and proteolysis (37, 38). Specifically, in males, TRA-1 is subject to proteasomal degradation. In hermaphrodites, however, TRA-1 is processed and phosphorylated, which generates a stable and active TRA-1 fragment capable of controlling transcription. Currently it is unclear when during embryonic development active TRA-1 protein is first generated in hermaphrodites. However, experiments using a temperature-sensitive loss-of-function mutation of the gene tra-2, which acts upstream of tra-1 in somatic sex determination, suggest that active TRA-1 might be generated in hermaphrodites starting at ~320 min after the first cell division (39). This notion is supported by the finding that the ceh-30 gene, whose expression is directly repressed by TRA-1, is no longer expressed at ~360 min (Figure 5, Figure 7). Based on these observations, we propose that the CEMs die only at ~470 min, because a level of active TRA-1 first has to be generated in the CEMs in hermaphrodites that is sufficient for the transcriptional repression of ceh-30, which is a prerequisite for the transcriptional de-repression of egl-1 and ced-3 transcription at ~390 and 460 min, respectively, and, hence, apoptosis induction (Figure 7). Hence, we propose that the timing of the CEM death is controlled by the sex determination pathway and, in particular, its terminal, global regulator, the Gli-like transcription factor TRA-1.


Transcriptional upregulation of both egl-1 BH3-only and ced-3 caspase is required for the death of the male-specific CEM neurons.

Nehme R, Grote P, Tomasi T, Löser S, Holzkamp H, Schnabel R, Conradt B - Cell Death Differ. (2010)

Model of the life-versus-death decision in the CEMsTop panel. Most cells programmed to die do so ~30 min after being generated. In these cells, proCED-3 protein inherited from the progenitor is sufficient for apoptosis induction in response to egl-1 transcriptional activation. Bottom panel. The CEMs in hermaphrodites die ~150 min after being generated (~470 min after the first cell division). Increasing TRA-1 activity results in decreasing CEH-30 activity, which is required for the de-repression of egl-1 and ced-3 transcription. The activation at the transcriptional level of the ced-3 gene compensates for decreased levels of proCED-3. See text for details.
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Related In: Results  -  Collection

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Figure 7: Model of the life-versus-death decision in the CEMsTop panel. Most cells programmed to die do so ~30 min after being generated. In these cells, proCED-3 protein inherited from the progenitor is sufficient for apoptosis induction in response to egl-1 transcriptional activation. Bottom panel. The CEMs in hermaphrodites die ~150 min after being generated (~470 min after the first cell division). Increasing TRA-1 activity results in decreasing CEH-30 activity, which is required for the de-repression of egl-1 and ced-3 transcription. The activation at the transcriptional level of the ced-3 gene compensates for decreased levels of proCED-3. See text for details.
Mentions: One obvious question that arises from our studies is why CEMs survive for ~150 rather than ~30 min before they undergo apoptosis. The CEMs are born ~320 min after the first cell division and die in hermaphrodites at ~470 min (12). The TRA-1 protein plays a pivotal role in the life-versus-death decision of the CEMs. In the CEMs, TRA-1 represses ceh-30 transcription thereby causing egl-1 and ced-3 de-repression and apoptosis induction. The activity of TRA-1 is regulated at the post-translational level by sex-specific cleavage and proteolysis (37, 38). Specifically, in males, TRA-1 is subject to proteasomal degradation. In hermaphrodites, however, TRA-1 is processed and phosphorylated, which generates a stable and active TRA-1 fragment capable of controlling transcription. Currently it is unclear when during embryonic development active TRA-1 protein is first generated in hermaphrodites. However, experiments using a temperature-sensitive loss-of-function mutation of the gene tra-2, which acts upstream of tra-1 in somatic sex determination, suggest that active TRA-1 might be generated in hermaphrodites starting at ~320 min after the first cell division (39). This notion is supported by the finding that the ceh-30 gene, whose expression is directly repressed by TRA-1, is no longer expressed at ~360 min (Figure 5, Figure 7). Based on these observations, we propose that the CEMs die only at ~470 min, because a level of active TRA-1 first has to be generated in the CEMs in hermaphrodites that is sufficient for the transcriptional repression of ceh-30, which is a prerequisite for the transcriptional de-repression of egl-1 and ced-3 transcription at ~390 and 460 min, respectively, and, hence, apoptosis induction (Figure 7). Hence, we propose that the timing of the CEM death is controlled by the sex determination pathway and, in particular, its terminal, global regulator, the Gli-like transcription factor TRA-1.

Bottom Line: We found that in the CEMs, the transcriptional activation of both the egl-1 and ced-3 gene is necessary for apoptosis induction.Furthermore, we identified three genes, unc-86, lrs-1, and unc-132, which encode a POU homeodomain transcription factor, a leucyl-tRNA synthetase, and a novel protein with limited sequence similarity to the mammalian proto-oncoprotein and kinase PIM-1, respectively, that promote the expression of the ceh-30 gene in the CEMs. On the basis of these results, we propose that egl-1 and ced-3 transcription are coregulated in the CEMs to compensate for limiting proCED-3 levels, which most probably are a result of proCED-3 turn over.Finally, we present evidence that the timing of the death of the CEMs is controlled by TRA-1 Gli, the terminal global regulator of somatic sexual fate in C. elegans.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Dartmouth Medical School, Norris Cotton Cancer Center, Hanover, NH 3755, USA.

ABSTRACT
Most of the 131 cells that die during the development of a Caenorhabditis elegans hermaphrodite do so approximately 30 min after being generated. Furthermore, in these cells, the pro-caspase proCED-3 is inherited from progenitors and the transcriptional upregulation of the BH3-only gene egl-1 is thought to be sufficient for apoptosis induction. In contrast, the four CEM neurons, which die in hermaphrodites, but not males, die approximately 150 min after being generated. We found that in the CEMs, the transcriptional activation of both the egl-1 and ced-3 gene is necessary for apoptosis induction. In addition, we show that the Bar homeodomain transcription factor CEH-30 represses egl-1 and ced-3 transcription in the CEMs, thereby permitting their survival. Furthermore, we identified three genes, unc-86, lrs-1, and unc-132, which encode a POU homeodomain transcription factor, a leucyl-tRNA synthetase, and a novel protein with limited sequence similarity to the mammalian proto-oncoprotein and kinase PIM-1, respectively, that promote the expression of the ceh-30 gene in the CEMs. On the basis of these results, we propose that egl-1 and ced-3 transcription are coregulated in the CEMs to compensate for limiting proCED-3 levels, which most probably are a result of proCED-3 turn over. Similar coregulatory mechanisms for BH3-only proteins and pro-caspases may function in higher organisms to allow efficient apoptosis induction. Finally, we present evidence that the timing of the death of the CEMs is controlled by TRA-1 Gli, the terminal global regulator of somatic sexual fate in C. elegans.

Show MeSH