Apoptosis-mediated cell death within the ovarian polar cell lineage of<i>Drosophila melanogaster</i>

Besse, Florence; Pret, Anne-Marie

doi:10.1242/dev.00313

Cited by 59 publications

(81 citation statements)

References 41 publications

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“…Both wild-type and hsp70: GAL4 alone had a few DCP-1-positive polar follicle cells, which undergo developmental cell death before stage 6 (Figures 3a and f). 49 Expression of p53A or p53B isoforms resulted in a significant increase in the number of apoptotic cells, with overexpression of p53B again having the strongest effect, whereas p53D and p53E did not induce apoptosis significantly (Figures 3b-f). Co-labeling for the Myc epitope tag indicated that all the isoforms were highly expressed and concentrated in a subnuclear compartment adjacent to the heterochromatic chromocenter (Figures 3b-e).…”

Section: Resultsmentioning

confidence: 92%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

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Section: Resultsmentioning

confidence: 92%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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“…To subtract out the normal background of developmental cell death that occurs for a small number of polar follicle cells, we counted the number of ovarioles that had greater than five apoptotic follicle cells between stages 1 and 5 (Besse and Pret 2003). Seven hours after one 30-min heat induction of hsp70:Myc:FL-Dup, a large fraction of ovarioles had widespread follicle cell death in the mitotic stages (97% of ovarioles), but many fewer ovarioles had greater than five dead cells in the hsp70:Myc:FL-Dup strain without heat induction (6% of ovarioles) or after heat treatment of control strains that lacked the transgene (0% of ovarioles) ( Fig.…”

Section: Rereplication Results In Caspase Activation and Apoptosis Inmentioning

confidence: 99%

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

130

155

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Initiation of DNA replication at origins more than once per cell cycle results in rereplication and has been implicated in cancer. Here we use Drosophila to examine the checkpoint responses to rereplication in a developmental context. We find that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage. In most cells, this rereplication triggers caspase activation and apoptotic cell death mediated by both p53-dependent and -independent pathways. Elevated Dup also caused DNA damage in endocycling cells, which switch to a G/S cycle during normal development, indicating that rereplication and the endocycling DNA reduplication program are distinct processes. Unexpectedly, however, endocycling cells do not apoptose regardless of tissue type. Our combined evidence suggests that endocycling apoptosis is repressed in part because proapoptotic gene promoters are silenced. Normal endocycling cells had DNA lesions near heterochromatin, which increased after rereplication, explaining why endocycling cells must constantly repress the genotoxic apoptotic response. Our results reveal a novel regulation of apoptosis in development and new insights into the little-understood endocycle. Similar mechanisms may operate during vertebrate development, with implications for cancer predisposition in certain tissues.[Keywords: DNA replication; DNA damage; endocycle; checkpoint; apoptosis] Supplemental material is available at http://www.genesdev.org. The timely duplication of the genome during S phase of every cell division cycle requires that DNA replication initiate from thousands of origins. If too few origins initiate, replication forks can collapse, resulting in DNA damage and incomplete replication of the genome. Initiation of DNA replication from origins more than once per cell cycle, however, results in "rereplication" and subsequent DNA damage (Arias and Walter 2007). In recent years, it has become increasingly apparent that problems with DNA replication are common in premalignant cells, with subsequent checkpoint defects leading to genome instability and cancer (Dutta 2007). It remains unclear, however, whether all cells in development are equivalent with respect to their regulation of DNA replication and checkpoint responses. Here, we use Drosophila to investigate the checkpoint responses to rereplication in a developmental context. Two important steps in the cell cycle regulation of DNA replication are the assembly and activation of a prereplicative complex (pre-RC) (Sivaprasad et al. 2006). The pre-RC assembles onto origins in early G1 and is subsequently activated in S phase. During pre-RC assembly, the hexameric origin recognition complex (ORC) serves as a scaffold for origin association of Cdc6 and Cdt1, which are both required to load the hexameric minichromosome maintenance complex (MCM), the replicative helicase (Randell et al. 2006;Sivaprasad et al. 2006). Once the MCM complex is tightly bound, the origins are considered to be "licensed" and competent to initiate replic...

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“…13 It is thus possible that hid function is necessary for primary induction of PC apoptosis and that reaper function participates to a secondary amplification loop that insures completion of PC elimination. In addition, we have been able to establish a link between hid function and Diap1 regulation in PC apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 During early stages of oogenesis, PCs undergo a highly regulated cell death program, whereby a small excess of PCs that is produced (1-4 supernumerary cells) is eliminated by apoptosis such that by mid-oogenesis 100% of the follicles contain exactly two PCs at each anterior and posterior extremity. 13 This restriction fulfills a physiological role as inducing prolonged survival of supernumerary PCs by blocking apoptosis leads to follicular cell patterning defects including recruitment of excess border cells and perturbed migration of these cells. 13 PCs thus represent an interesting model to study how cell survival/death choices are made, in particular, in the context of a whole organ.…”

mentioning

confidence: 99%

“…13 This restriction fulfills a physiological role as inducing prolonged survival of supernumerary PCs by blocking apoptosis leads to follicular cell patterning defects including recruitment of excess border cells and perturbed migration of these cells. 13 PCs thus represent an interesting model to study how cell survival/death choices are made, in particular, in the context of a whole organ. We have undertaken a genetic and cellular analysis of PC apoptosis to identify which of the known components of the core cell death machinery are specifically involved in PC apoptosis and which represents regulatory points.…”

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confidence: 99%

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Physiological apoptosis of polar cells during Drosophila oogenesis is mediated by Hid-dependent regulation of Diap1

et al. 2010

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Although much has been learned in recent years about the apoptotic machinery, the mechanisms underlying survival and death choices during development of metazoans remain less clearly understood. During early oogenesis in Drosophila, a small excess in the number of specialized somatic cells, called polar cells (PCs), produced at follicle extremities is reduced to exactly two cells through apoptosis by mid-oogenesis. We have found that PCs destined to die first lose their apical contacts and then round up and shrink progressively until they disappear. Caspases are activated only once the cells have begun to shrink, suggesting that they are implicated in this part of the process, but not in the initial loss of cell polarity. Loss-of-function analyses based on mutant, clonal and RNAi approaches show that among the RHG family of pro-apoptotic factors, Hid is specifically necessary for PC apoptosis, as well as the initiator caspase Dronc and its adaptor Dark/Apaf-1, and likely several effector caspases, in particular Drice. In addition, we show that Hid protein and transcripts accumulate specifically in PCs destined to die, while the anti-apoptotic factor Diap1 is downregulated in these cells in a hid-dependent manner. Therefore, our results implicate the Hid-Diap1 module as an important regulatory point in a developmental case of apoptosis.

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Apoptosis-mediated cell death within the ovarian polar cell lineage ofDrosophila melanogaster

Cited by 59 publications

References 41 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Physiological apoptosis of polar cells during Drosophila oogenesis is mediated by Hid-dependent regulation of Diap1

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