pelo was identified in a genetic screen looking for genes that can suppress dpp overexpression-induced GSC-like tumors, suggesting that pelo must somehow genetically interact with the dpp/Bmp pathway. To further reveal the relationship between pelo and Bmp signaling, the dose effect of pelo on dpp-induced GSC-like tumor formation was carefully examined. As reported previously (Xie, 1998; Song, 2004), ovarioles overexpressing dpp by the c587 gal4 driver contain only single germ cells resembling GSCs. Among the dpp-overexpressing ovarioles also carrying one copy of the pelo1 mutation, 36% of them showed the same tumor phenotype, but the rest of the ovarioles contained differentiated germline cysts, developing egg chambers and even mature eggs, which could explain why pelo was identified in the suppressor screen. Among the dpp-overexpressing ovarioles also carrying two copies of the pelo1 mutations, only 13.8% of them contained only GSC-like single germ cells, while 49.8% of them had a mixture of single germ cells and developing cysts. Interestingly, the rest (36.4%) were reminiscent of the pelo GSC loss phenotype only. These results suggest that pelo functions as one of the Bmp downstream components or in a pathway parallel to the Bmp signaling pathway to control GSC self-renewal (Xi, 2005).
To further understand how pelo modulates Bmp signaling activity, the expression of a Bmp direct target gene, Dad, was examined in the pelo mutant GSCs. Dad-lacZ is a lacZ enhancer trap line for Dad. Its expression is the strongest in the GSCs, and is quickly downregulated in the differentiating cystoblasts. The pelo1 mutant GSCs marked by loss of ubi-GFP expression were generated by the FLP-mediated FRT recombination, and then were analyzed for Dad-lacZ expression 2 weeks after clone induction. Consistent with the idea that pelo is involved in modulating Bmp signaling, 69% of the marked mutant pelo GSCs (GFP negative) showed the downregulation of Dad-lacZ expression in comparison with their neighboring wild-type GSCs (GFP-positive). It was further asked whether pelo is also involved in Bmp-mediated bam repression in GSCs, since Bmp signaling has been shown to directly represses bam transcription in GSCs. A bam-GFP transgene (a GFP reporter driven by a bam promoter) is repressed in GSCs, while its expression is upregulated in the differentiating cystoblasts (Chen, 2003b). The marked pelo mutant GSCs (lacZ negative) were generated by the FLP-mediated FRT recombination and were examined for bam expression. Only about 5% of the marked pelo mutant GSCs (lacZ negative) showed slight upregulation of bam-GFP in comparison with their neighboring unmarked wild-type GSCs (lacZ positive), while the rest of the marked pelo1 mutant GSCs did not upregulate bam-GFP expression. These findings indicate that Pelo is involved in modulating Bmp signaling in GSCs but plays little or no role in regulating Bmp-mediated bam repression, and further suggest that it functions in one branch of the responses of the Bmp signaling pathway to regulate GSC self-renewal (Xi, 2005).
The pelota transcript is present in all developmental stages examined, but is most abundant in 0-2 hour old embryos and adults. The larval transcript appeared larger in some, but not all, northern blot experiments. The 2.1 kb transcript is present in the germlineless progeny of oskar mutant flies and in iab4 flies that lack a gonad. Thus the pelota transcript is not restricted to the germline or gonad. In pelo mutant adults both genomic and cDNA probes detected only a 1.1 kb transcript, presumably a truncation of the 2.1 kb transcript due to insertion of the transposon (Eberhart, 1995).
During Drosophila spermatogenesis, germ cells undergo four rounds of mitosis, an extended premeiotic G2 phase and two meiotic divisions. In males homozygous for mutations in pelota, the germline mitotic divisions are normal, but the cell cycle arrests prior to the first meiotic division; pelota males are therefore sterile. Chromosomes begin to condense in these mutants, but other meiotic processes, including nuclear envelope breakdown and spindle formation, do not occur. The arrest phenotype closely resembles that of mutations in the Drosophila cdc25 homolog Twine. Although meiosis is blocked in pelota and twine homozygotes, spermatid differentiation continues. pelota is also required for patterning in the eye and mitotic divisions in the ovary. The pelota locus has been cloned and shown to encodes a 44x103 Mr protein with yeast, plant, worm and human homologs (Eberhart, 1995).
In males homozygous for pelo1, the cell cycle in spermatocytes arrests either just before or very early in the first meiotic cell division. The apical regions of a testis from a pelo1 homozygote appear normal, filled with visibly wild-type mitotic and growth phase cysts. The rest of the testis, which usually contains 64-cell spermatid cysts, is instead filled with 16-cell cysts. The spermatocytes attain their mature size. Furthermore, they undergo a premeiotic S phase, as evidenced by the incorporation of bromodeoxyuridine into 16-cell cysts in pelota testes. However, meiotic figures, which can be easily recognized in squashed preparations of wild-type testes, are never seen (Eberhart, 1995).
While meiotic divisions do not occur in pelo1 spermatocytes, other aspects of spermatogenesis continue, resulting in 4N spermatids. In wild-type testes, the round, dark nebenkern is the first major cytoplasmic structure to form after meiosis. It is made up of mitochondria and serves as a marker for postmeiotic cytoplasmic development. Germline cells in pelo1 testes develop into 4N spermatids containing nebenkerne. As nebenkerne form, the pelo1 nuclei shrink in size by one third to spermatid head and tail structures. The content of testes from flies trans-heterozygous for pelo1 and Df(2L)30A;C, a deficiency for the pelota region, are indistinguishable from those of pelo1 homozygotes. Thus, pelo1 is a strong allele and possibly a null (Eberhart, 1995).
The pelo1 testis phenotype -- limited spermatid development in the absence of meiosis -- closely resembles that of a mutation in the cell cycle gene twine. Although the proportion of 4N spermatids with head and tail structures is greater for twine mutation than for pelo1, other pelota alleles, generated by remobilization of the pelo1 P element have a phenotype identical to that of the twine allele. The tails of 4N spermatids elongate significantly and the nuclei form wedge-shaped heads. The heads are larger than in wild type, fail to cluster normally and are not attached to the tails (Eberhart, 1995).
A weaker class of pelota mutations, in which some meioses, albeit aberrant, occur, was also generated by mobilization of the pelo1 P element. Spermatids from weak pelota homozygotes commonly contain two or four nuclei in a single cell, indicating a failure of cytokinesis in one or both meiotic divisions. Variations in nuclear size, reflecting defects in chromosome segregation, are also seen. Defects within a given cyst are usually heterogeneous, with some cells displaying meiotic defects while others appear wild type or are arrested before meiosis I (Eberhart, 1995).
In summary, during spermatogenesis, the mitotic divisions and subsequent growth phase appear normal in pelota mutants. The first apparent defect is a failure of meiotic cell division, resulting in the accumulation of arrested spermatocytes. The cell cycle arrest occurs early in meiosis; no metaphase or anaphase figures can be seen. Some aspects of spermiogenesis continue, resulting in 4N spermatids with head and tail structures, a phenotype identical to twine mutants (Eberhart, 1995).
To define the arrest point of pelota in greater detail, three landmark events occurring at meiosis I were analyzed: chromosome condensation, spindle formation and nuclear envelope breakdown. The analysis of the pelota mutant phenotype was facilitated by similar studies on twine and by a detailed description of chromosome and microtubule movements in spermatogenesis. During the spermatocyte growth phase leading up to meiosis, the two autosomes in each spermatocyte nucleus are visible as diffuse, mesh-like structures, while the sex chromosomes are associated with the nucleolus and often appear more punctate. Chromosome condensation occurs rapidly late in prophase; chromosomes condense on the periphery of the nucleus, compacting until they appear as dots. After the chromosomes have fully condensed they move inward to the center of the nucleus, appearing as a single mass. In arrested pelota spermatocytes, the chromosomes partially condense, but never move away from the nuclear periphery. The same levels of DNA condensation are observed in arrested twine spermatocytes (Eberhart, 1995).
A second critical meiotic event is nuclear envelope breakdown. The nuclear lamins are associated with the nuclear envelope in mature spermatocytes. During meiosis, the nuclear envelope breaks down and nuclear lamins disperse, forming diffuse clouds around the chromatin; after meiosis the nuclear lamins associate with the reformed nuclear envelope. As spermatids continue to develop, nuclear lamin staining is lost. The nuclear envelope does not break down in arrested pelota spermatocytes. In strong pelota alleles, heavy nuclear staining is seen in spermatocytes whose condensed chromosomes indicate they have just arrested in late meiotic prophase. Nuclear lamin staining is still present after the nebenkerne form. In pelota 4N spermatids that develop shaped head structures and elongate tails, lamin staining becomes fragmented and disappears. The fate of nuclear lamins in twine resembles that in pelota: the nuclear envelope remains intact at the initial arrest, the nuclear lamins are then degraded in conjunction with sperm head and tail formation (Eberhart, 1995).
Formation of the spindle is a third event central to meiotic cell division. During the spermatocyte growth phase, microtubules form a diffuse cytoplasmic network; this network persists until the cells mature. Late in meiotic prophase the centrosomes separate and move toward the poles; after they reach the poles the cytoplasmic tubulin network breaks down and a spindle is formed. In arrested pelota spermatocytes, the microtubules remain in the cytoplasm. The centrosomes separate, but don't complete their migration and nucleate no significant asters; a spindle is never observed. An identical phenotype is reported for twine mutants (Eberhart, 1995).
These studies indicate that spermatogenesis in pelota and twine homozygotes is normal until late meiotic prophase, at which point the cell cycle arrests. No spindles form in these mutants and the nuclear lamins do not disperse or degrade until significant spermatid differentiation has occurred. Not all meiotic events are blocked, however, since some chromosome condensation is seen. Cytoplasmic structures that in wild type form after meiosis (such as nebenkerne, shaped heads and elongated tails) develop in these 4N spermatids (Eberhart, 1995).
In flies homozygous for strong pelota alleles, the eyes are often rough, with disordered ommatidial arrays and bristles. In addition, the eyes of pelota homozygotes are up to 30% smaller than those of heterozygous siblings. The severity of the eye defects varies between flies: some homozygotes have eyes that appear wild type. These results demonstrate that pelota is required for Drosophila eye development (Eberhart, 1995).
dpp overexpression in inner sheath cells driven by the c587-gal4 driver has been shown to completely block germ cell differentiation, resulting in the formation of GSC-like tumors and consequently female sterility (Song, 2004). Such female sterility is very sensitive to genetic changes of any dpp downstream components; for example, removal of one copy of any Bmp downstream gene such as punt, mad and Med can sufficiently reverse the sterility phenotype, leading to fertile females. To identify the genes that are potentially involved in Bmp signaling in GSCs, a dominant suppressor screen was conducted using the existing deficiency kit, which covers 65% of the Drosophila genome. In the screen, a small deficiency [ Df(2L)s1402 (30C-30F)] was identified that can rescue dpp overexpression-induced female sterility. Among 19 existing mutations in the genomic region, pelota is identified as dominantly suppressing dpp overexpression-induced sterility. Although it has been identified for its role in Drosophila male meiosis, its mutant females are also semi-fertile, and ovaries are overtly small (Eberhart, 1995), suggesting that it is also involved in the regulation of Drosophila oogenesis. However, it remains unclear whether the pelo mutation affects GSCs (Xi, 2005).
To determine if pelo is required for maintaining GSCs, GSCs were quantitated in pelo1 homozygous mutant germaria. pelo1 is a P-element-induced strong or null allele, which is based on the evidence that it produces a truncated pelo transcript deleting most of the eRF1alpha domain (Eberhart, 1995). The ovaries from 2-day-old or 7-day-old pelo1 homozygous and heterozygous females were immunostained with anti-Vasa and anti-Hts antibodies. Vasa is expressed specifically in germ cells, while Hts is preferentially rich in spectrosomes (GSCs and cystoblasts), fusomes (2-, 4-, 8- and 16-cell germline cysts) and membranes of somatic follicle cells in the germarium and egg chambers. GSCs can be reliably identified at the tip of the germarium by their anteriorly localized spectrosome and direct contact with cap cells. In pelo1 heterozygous control females, 2-day-old and 7-day-old germaria had an average of 2.35 and 2.40 GSCs, respectively, and more than 97% of the germaria contained two or more GSCs, which closely resembles wild-type. The 2-day-old pelo1 homozygous germaria contained an average of 1.4 GSCs, with some having two GSCs and others containing only one, indicating that pelo is required for GSC establishment or GSC maintenance. Furthermore, the 7-day-old pelo1 germaria had an average of 0.47 GSCs with 57.3% (51/89) of them containing no GSC. Consistent with the previous study showing that pelo1 is a strong or null allele (Eberhart, 1995), the pelo1/df(2L)s1402 mutant ovaries behaved just like the homozygous pelo1 mutant ovaries in terms of GSC numbers at different ages. This also suggested that the mutation in pelo is responsible for GSC loss phenotype in the pelo1 homozygous mutant ovaries. Together, these results demonstrate that Pelo is required for maintaining GSCs in the Drosophila ovary (Xi, 2005).
Pelo could maintain GSCs by controlling either self-renewal or survival. Thus, the GSC loss in pelo mutant ovaries could be due to either differentiation or cell death. To differentiate these two possibilities, cell death of GSCs was examined in the pelo mutant ovaries using the ApoTag cell death labeling system, which has been successfully used in previous studies (Zhu, 2003). In this experiment, the spectrosomes and fusomes were also labeled for facilitating identification of GSCs, cystoblasts and germline cysts. Among 156 pelo1 heterozygous control germaria, no dying GSCs (>250 GSCs examined) were observed, and there were eight dying cysts. This is consistent with the previous result that some germline cysts die naturally (Drummond-Barbosa, 2001). Among 264 pelo1 homozygous germaria, there were also no dying GSCs detected (>300 GSCs examined) but 49 dying cysts were observed. Clearly, the pelo mutation does not affect GSC survival but appears to increase dying cysts [from 5% of the 2-day-old wild-type germaria carrying dying cysts (n=40) to 18% of the 2-day-old pelo1 mutant garmaria carrying dying cysts (n=89)]. These observations suggest that Pelo is required for GSC self-renewal and also for cyst survival (Xi, 2005).
It was also noticed that the pelo mutant germaria that still harbor two GSCs were extremely small and contained very few germline cysts. Since the pelo mutation results in only 18% of the germaria carrying one or more dying cysts, the pelo mutant GSC division rate probably also decreased. Then, BrdU incorporation was used to label S-phase cells to determine whether pelo is required for controlling GSC division. In the 2-day-old females, 10.7% of pelo heterozygous control GSCs were BrdU positive, whereas only 2.5% of pelo homozygous GSCs incorporated BrdU. This result shows that pelo is also required for controlling GSC division (Xi, 2005).
Pelo could control GSC self-renewal by acting either inside the GSC, in the niche, or in both. mRNA in situ hybridization and gene expression profiles of agametic ovaries show that pelo mRNAs were ubiquitously expressed at lower levels throughout the germarium, suggesting that pelo could function in GSCs or the somatic niche cells, or both. FLP-FRT-mediated mitotic recombination was used to determine whether Pelo functions inside GSCs for controlling their self-renewal. The FLP-mediated FRT recombination has been used to generate marked mutant GSCs and determine their loss rates for deducing the role of a particular gene in GSC maintenance (Xie, 1998). According to published experimental procedures (Xie, 1998; Song, 2002a), the ovaries of the females of appropriate genotypes were dissected at 3, 10, 17 and 24 days after clone induction (ACI) mediated by heat-shock treatments, and marked wild-type and pelo mutant GSCs were identified by the lack of arm-lacZ expression and the presence of an anteriorly anchored spectrosome. In the wild-type control, 55.0% of the marked GSCs (from 52.8% of the germaria carrying one or more marked control GSCs at 3 days ACI to 28.9% of the germaria carrying one or more marked control GSCs at 24 days ACI) were still maintained for 3 more weeks (Xie, 1998). By contrast, 97% of the marked pelo mutant GSCs (from 48.6% of the germaria carrying one or more marked mutant GSCs at 3 days ACI to 1.7% of the germaria carrying one or more marked mutant GSCs at 24 days ACI) were lost during the same three week period. These results demonstrate that pelo is required in GSCs for controlling their self-renewal. It appears that these marked pelo mutant GSCs are lost slower than the GSCs in the homozygous pelo mutant ovaries. This could be explained by the possibility that Pelo is very stable or has functions in both GSCs and soma. If Pelo is very stable, it takes longer for residual wild-type Pelo that is made before clone induction to be degraded in the marked pelo mutant GSCs (Xi, 2005).
To confirm further that Pelo is indeed required intrinsically for controlling GSC self-renewal and that the pelo mutation is responsible for the GSC loss phenotype, a UASp-pelo transgene was expressed specifically in the germ cells using a germ cell-specific GAL4 driver, nos-gal4VP16, in pelo mutant ovaries. A UASp-pelo construct was made to be expressed in germline or soma using different GAL4 drivers; nosgal4-VP16 can drive a UAS transgene to be expressed in both GSCs and later germ cell cysts. Interestingly, introduction of one copy of UASp-pelo transgene alone into the pelo homozygous females was able to partially rescue the GSC loss phenotype, suggesting that there is a leaky expression of the transgene even without a GAL4 driver. The stem cell loss phenotype in pelo mutant ovaries was fully rescued by nosgal4VP16-driven pelo expression in the germline, including GSCs, restoring the normal GSC number. This result shows that the mutation in pelo is responsible for the GSC loss phenotype, and further confirms that pelo is required intrinsically for controlling GSC self-renewal (Xi, 2005).
Although pelo is required intrinsically for controlling GSC self-renewal, it does not rule out the possibility that a somatic function of pelo is also involved in regulating GSC self-renewal since it is also expressed in the somatic cells of the germarium. Initially, whether the pelo mutation affects the survival of cap cells was examined. A hh-lacZ enhancer trap line used in this study has been used to label terminal filament cells and cap cells in the Drosophila ovary. In the pelo homozygous germaria carrying one or no GSCs, the cap cell number appeared to be normal, ranging from five to seven, indicating that Pelo function is at least not required for the formation or survival of cap cells. However, pelo could still be required in the surrounding somatic cells for controlling GSC function through regulating production of signals. To further test whether pelo has a somatic function in GSC regulation, the c587-gal4 driver, which is expressed in IGS cells and follicle progenitor cells, and the same UASp-pelo transgene were used to test whether somatic expression pelo can rescue the pelo mutant GSC loss phenotype. However, c587-driven pelo expression in the somatic cells could only confer very limited rescue of the pelo mutant GSC loss phenotype, in addition to the partial rescue conferred by the UAS-pelo transgene alone, suggesting that pelo has little role in IGS cells and follicle cell progenitors for GSC self-renewal. It has not been tested whether pelo expression in terminal filaments/cap cells can mitigate the GSC loss phenotype of the pelo mutant ovaries; the results can not completely rule out the possibility that Pelo has a function in somatic cells for controlling GSC self-renewal (Xi, 2005).
Since pelo is expressed in all the somatic cells, including SSCs, whether pelo has a role in SSC maintenance was tested using FLP-mediated FRT recombination to generate marked pelo mutant SSC clones. The marked SSCs were identified as the arm-lacZ-negative somatic cells residing at the 2a/2b boundary and generating arm-lacZ-negative (marked) follicle cells in the germarium and egg chambers, according to previous studies (Song, 2002a; Song, 2003). In the control, 68% of marked wild-type SSCs were maintained for 3 weeks, supporting the fact that SSCs have a slow natural turnover. Similarly, 62% of the marked pelo SSCs were maintained for 3 weeks, indicating that pelo plays little or no role in SSC maintenance. The marked pelo1 mutant follicle cell clones exhibited a very minor phenotype: they appeared slightly thinner compared with wild-type follicle cells. Although pelo is ubiquitously expressed throughout the germarium, the main function of pelo is primarily restricted to GSCs and their progeny in the ovary (Xi, 2005).
Drosophila Pelo has a putative nuclear localization signal sequence (PRKRK) at its N terminus; this sequence is perfectly conserved from Drosophila to human, raising an interesting possibility that Pelo is a nuclear protein. If Pelo indeed functions in the nucleus, it would be expected that the disruption of the putative nuclear localization sequence would lead to loss of its function. To directly test the idea, a mutant version of Pelo was generated with the replacement of PRKRK by RSRS, since ablation of helix-breaking residue proline and reduction of basic residues can abolish the function of the nuclear localization signal. In S2 cells, the mutant Pelo protein tagged with 3xFlag and 6xMyc at its N terminus [F-M-Pelo(nls*)] was localized in the cytoplasm in the same way as the wild-type version tagged with the same tags at its N terminus (F-M-Pelo). To further determine whether the NLS of Pelo is important for Pelo function in controlling GSC self-renewal in vivo, transgenic flies were generated carrying either UASp-F-M-Pelo or UASp-F-M-Pelo(nls*). Two independent insertion lines for UAS-F-M-Pelo could fully rescue the pelo mutant GSC loss phenotype when they were driven to be expressed specifically in the germ cells by nos-gal4VP16, indicating that FLAG and MYC tags do not interfere with Pelo function. Similarly, two independent transgenic lines of the NLS mutated version of Pelo could also fully rescue the pelo GSC loss phenotype, further supporting that the putative NLS is not important for Pelo function in GSCs and that Pelo functions in the cytoplasm to control GSC self-renewal. Interestingly, one of the transgenic lines [UASp-FM(nls*)#1] showed complete rescue for the pelo GSC loss phenotype with the nosgal4VP16 driver, whereas it exhibited little rescue for the GSC loss phenotype of the pelo mutant ovaries with the c587 driver or without any gal4 driver, further supporting the earlier conclusion that the mutation in the pelo gene is responsible for the GSC loss (Xi, 2005).
Since the tagged Pelo is functional, the Pelo subcellular localization in GSCs was determined using Flag or Myc antibodies. As in S2 cells, Pelo is mainly expressed in the cytoplasm in the germ cells. Since Pelo protein has a domain showing homology to translation release factor 1a (RF1), whether Pelo is associated with the ER was examined. Sec61alpha-GFP, a GFP fusion protein localized to ER membrane, is localized to ER membrane rich in the peri-nuclear area and spectrosome area of the GSC, while Pelo is evenly distributed throughout the cytoplasm of the GSC. There was only limited pattern overlap between Sec61alpha-GFP and F-M-Pelo, indicating that Pelo is primarily localized to the cytoplasm away from the ER membrane. Consistently, Pelo was also localized to the cytoplasm in S2 cells. These findings show that Pelo functions in the cytoplasm of GSCs to control their self-renewal (Xi, 2005).
It was noticed that the pelo mutant females have some fertility after eclosion and quickly loose their fertility. Interestingly, in the 2-day-old pelo mutant ovaries, early egg chambers look largely normal, and even a few mature eggs are present. By contrast, in the 7-day-old ovaries, egg chambers older than stage 9 are rarely observed, and even those early stage egg chambers exhibit condensed nurse cell DNA: this suggests that the egg chambers are in the process of undergoing apoptosis. The egg chamber degeneration is not due to oocyte formation defect because in these egg chambers the oocyte is present. In addition, the size of some egg chambers exhibiting condensed nurse cell DNA is also smaller than normal. The Pelo function also appears to be germ-cell specific in egg chambers, since marked mutant pelo germ cells fail to grow to the normal size and become apoptotic. These results indicate that pelo is also required in the germ cells for their survival or normal differentiation during later oogenesis (Xi, 2005).
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date revised: 30 March 2006
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