Department of Biochemistry, University of Washington, J591, HSB, Seattle, WA 98195-7350, USA
*Author for correspondence (e-mail: hannele{at}u.washington.edu)
Accepted August 23, 2001
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SUMMARY |
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Key words: Drosophila, Notch, Delta, Cell cycle, Follicle cells
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INTRODUCTION |
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During Drosophila oogenesis, the Notch pathway plays multiple roles in specifying follicle cell groups, the terminal follicle cells, dorsal anterior follicle cells and polar cells (Ruohola et al., 1991; Xu et al., 1992; Bender et al., 1992; Larkin et al., 1996; Keller Larkin et al., 1999; Gonzalez-Reyes and St Johnston, 1998; Jordan et al., 2000). Our analyses of Notch function in the ovary have revealed a connection between Notch signaling and regulation of a transition from a mitotic cell cycle to an endoreplication cycle (this study). The endoreplication cycle, or endocycle, is a variation of the normal mitotic cell cycle, in which cells increase their genomic DNA content without dividing. The endocycle is widespread among multicellular organisms and uses much of the same G1/S regulatory machinery as mitotic cycles. The mechanism responsible for skipping over M phase during the endocycle is the subject of much current investigation (Edgar and Orr-Weaver, 2001). The follicle cells in the Drosophila ovary offer an excellent system in which to study the mitotic-to-endocycle transition. The Drosophila germline is surrounded by an epithelial follicle cell layer. The follicle cells undergo multiple rounds of mitotic divisions during the early stages of oogenesis. At stage 6, these cells switch from the normal mitotic cycle and undergo three rounds of endocycles. After the endocycles, most DNA is no longer replicated except the chorion genes, which continue to be amplified in a specific, tightly regulated fashion (Royzman and Orr-Weaver, 1998).
String is a Drosophila Cdc25-type phosphatase that triggers mitosis by dephosphorylating and thereby activating the Cdk1/Cyclin B kinase (Edgar et al., 1994). Differential expression of string regulates mitosis during most stages of Drosophila development: loss-of-function mutations in the gene cause G2 arrest in both embryos and imaginal disc cells (Edgar and OFarrell, 1989; Neufeld et al., 1998), whereas ectopic string expression in both embryo and discs drives G2 cells into mitosis (Edgar and OFarrell, 1990; Neufeld et al., 1998; Johnston and Edgar, 1998). These results suggest that String is rate limiting for mitotic initiation and therefore regulation of string expression is a key in controlling mitosis. The abundance of String protein is mainly controlled at the transcriptional level. Moreover, mutations in many patterning genes alter string expression in specific ways, indicating that string transcription is controlled by the same network of factors that controls cell fates (Arora and Nüsslein-Volhard, 1992; Edgar et al., 1994; Johnston and Edgar, 1998). The large upstream control region of the string gene has been dissected and shown to consist of many modular elements with separable activities (Lehman et al., 1999). These elements pattern mitoses in the embryo and in neural lineages at many stages of development. In some cases Drosophila String is functionally redundant with another Cdc25 homolog, Twine (Edgar and Datar, 1999). In addition to transcriptional regulation, String protein turnover and Twine translational levels can affect cell cycle transition (Mata et al., 2000; Seher and Leptin, 2000; Grosshans and Wieschaus, 2000; Maines and Wasserman, 1999).
We show that the transition from mitotic cycle to endocycle in the Drosophila follicle cell epithelium is regulated by the Notch pathway. Loss of Notch or its downstream transcription factor Su(H) in follicle cells, or its ligand Delta in the underlying germline, disrupts the normal transition of the follicle cells from mitotic cycle to endocycle, leading to overproliferation of these cells. A target of Notch and Su(H) is likely to be the G2/M cell cycle regulator string, as string is normally repressed in the follicle cells just before the endocycle transition but is expressed when Notch is inactivated. Analyses of the activity of string enhancer elements in follicle cells reveal the presence of an element that promotes expression of string until just before the onset of polyploidy in the wild-type follicle cells, but much beyond that in egg chambers that are lacking germline Delta. These results suggest that the string gene may be at least one of the targets of the endocycle-promoting activity of the Notch pathway.
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MATERIALS AND METHODS |
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Staining procedures
Ovaries were dissected in 1x phosphate-buffered saline (PBS) and fixed shaking for 20 minutes in 200 µl of 4% paraformaldehyde in PMES (0.1 M Pipes pH 6.9, 2 mM MgSO4, 1 mM EGTA) with 0.5% NP40 and 600 µl of Heptane. They were rinsed for 5 minutes with NP40 wash (50 mM Tris 7.4, 150 mM NaCl, 0.5% NP40, 1 mg/ml bovine serum albumin (BSA), 0.2% sodium azide) and blocked in 20% goat serum (in NP40 wash) for 2 hours at room temperature. The tissue was incubated with primary antibodies overnight at 4°C. The next day they were rinsed with NP40 wash four times, for 20 minutes each. They were then incubated with a secondary antibody for 2 hour at room temperature and stained with DAPI (1 µg/ml in NP40 wash), washed three times with NP40 wash (20 minutes each) and dissected onto slides in 70% glycerol, 2%NPG, 1xPBS. Confocal microscopy, X-gal staining and in situ hybridization was performed as described previously (Keller Larkin et al., 1999; Tworoger et al., 1999). stg cDNA (a gift from B. Edgar) was labeled with digoxigenin. A two-photon laser-scanning microscope (Leica TCS SP/MP) was used in this study.
The following antibodies were used: mouse anti-Armadillo (1:20, Developmental Studies Hybridoma Bank), mouse anti-FasciclinIII (1:20, Developmental Studies Hybridoma Bank), mouse anti-Cyclin B (1:20, Developmental Studies Hybridoma Bank), mouse anti-Notch intracellular domain (1:20, Developmental Studies Hybridoma Bank), mouse or rabbit anti-ß-gal (1:5000, Sigma), mouse anti-Broad-Complex Z1 (1:50, a gift from G. Guild), mouse anti-Delta (1:100) (Bender et al., 1993), rabbit anti-PH3 (1:200, Upstate Biotechnology), Alexa 488, 568 or 633 goat anti-mouse (1:500) and Alexa 568 or 633 goat anti-rabbit (1:500) (Molecular Probes).
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RESULTS |
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Delta from the germline is required for the mitotic to endocycle transition in follicle cells
To investigate the possibility that the Notch pathway is involved in the regulation of the mitotic cycle-to-endocycle transition, we first analyzed the expression of the Notch ligand, Delta, in oogenesis. Weak Delta expression is observed in follicle cells and germline from the germarium to stage 5 in oogenesis. At around stage 6, a dramatic upregulation of Delta expression is observed in the germline cells reaching the highest level at stage 7 (Fig. 2A) (Bender et al., 1993; Keller Larkin et al., 1999). This upregulation of Delta in the germline coincides with the transition from mitotic cell cycle to endocycle in the follicle cells (Fig. 2A, note the lack of PH3 in the egg chamber with high germ line Delta at stage 7).
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The glycosyltransferase Fringe is a modifier of the Delta-Notch interaction in imaginal discs (Bruckner et al., 2000; Moloney et al., 2000; Munro and Freeman, 2000; Blair, 2000), and in oogenesis of earlier Notch-dependent processes that allow pinching off to occur in the germarium and define the number of polar cells (Jordan et al., 2000; Zhao et al., 2000; C. A., W.-M. D., K. Jordan and H. R.-B., unpublished). When Fringe is present in Notch-expressing cells, Notch can be activated by low levels of Delta expression. Because Delta expression is upregulated in stage 6 germline cells, we suspected that Fringe would not be required for Delta-Notch signaling in this later case. Indeed, no CycB or PH3 staining was detected after stage 6 of oogenesis in fringe mutant clones (Table 1), suggesting that Fringe is not essential in the Delta-Notch interaction that regulates the transition from mitotic cycle to endocycle in follicle cells.
Su(H) but not E(spl) is required for cell cycle control
Does Notch exert its effect on the mitosis-endocycle transition through transcriptional regulation? Suppressor of Hairless (Su(H)) is a transcription factor that interacts with the cleaved-Notch-intracellular domain after Delta binds to the Notch extracellular domain. This interaction leads to transcription of downstream target genes, including Enhancer of Split (Espl) complex genes. We made follicle cell clones of a Su(H) hypomorphic allele and E(spl) null allele, then probed the egg chambers with anti-PH3 and CycB antibodies. As in Notch follicle cell clones, small nuclei, PH3 and CycB were observed in Su(H) clones (Fig. 4A-C; Table 1; 76%, n=46). No extra cell division was detected, however, in follicle cell clones mutant for E(spl) (Fig. 4D; Table 1). These results suggest that Notch and Su(H) regulate the follicle cell mitotic-to-endocycle transition but do not act through the E(spl) genes.
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Notch acts on the cell cycle transition through String
Mitosis in most Drosophila cells is triggered by brief bursts of transcription of string, which encodes a Cdc25-type phosphatase that activates the mitotic kinase, Cdk1 (Cdc2). Transcriptional control is an important mode of regulation for the activity of this G2/M controller. Fig. 1C shows that string is expressed in a patchy fashion when follicle cells are in the mitotic cell cycle but repressed when the follicle cells are in the endocycle. This repression requires Notch activity, as string mRNA is observed in egg chambers with Notch clones beyond the normal stage 6 in oogenesis (Fig. 3F).
To test whether String is essential for follicle cell mitotic cycles, we generated string mutant clones. The mutant clones had far fewer cells than sister clones (zero to two cells in mutant clones, 3-15 in sister clones, n=24, mutant:sister=0.1; Fig. 6F,H) and showed no expression of G2/M stage markers, suggesting that String is required for the follicle cell mitotic cycle. In control experiments, the mutant:sister ratio was 1.0 (n=10).
Previous studies have revealed that many cis-acting elements distributed over >30 kb upstream of string that control string transcription in different cells and tissue types (Lehman et al., 1999). To map the transcriptional control elements that regulate string in follicle cells, we took advantage of gene-fusion constructs in which the string locus was dissected into fragments and fused to lacZ reporter genes containing the basal 0.7 kb string promotor (Lehman et al., 1999). Of 11 different gene fusions tested, two showed specific expression in follicle cells. These constructs define the regions of the string promoter that are required for string expression and therefore for controlling the cell cycle in follicle cells (Table 2). Interestingly, R4.9 (4.9 kb region) exhibited expression in follicle cells of the germarium to around stage 2 in oogenesis, while R6.4 (6.4 kb region) showed expression beginning in stage 3 and abruptly terminating at the mitotic-to-endocycle transition in stage 6 (Fig. 6B-E; Table 2).
If the two enhancer elements (4.9 and 6.4; Fig.6A) are required for controlling two different bursts of cell divisions in follicle cells, then a rescue construct that covers only the first element should only partially rescue the division defects in string clones. That is exactly what we observed: when string clones were produced in the background of the 15.3 kb rescue construct (see Fig. 6A), mutant clones of half the size of sister clones were detected (one to six cells in mutant clones, 2-15 in sister clones, n=21, mutant:sister=0.49). This result suggests that the 4.9 kb element completely contained within the 15.3 kb rescue construct supports only the early expression and rescues the first but not the second burst of cell divisions in the follicle cell layer (Fig. 6G,I). Interestingly, the size of most of the nuclei in the clones was twice that of the nuclei typically observed in the sister clones or in the neighboring cells (Fig. 6G; 77%; wild-type nuclear volume/mutant nuclear volume=2.2), possibly suggesting an extra endoreplication cycle. After the action provided by the first string promoter element, the cells may have stopped dividing and as a default prematurely entered the endocycle program. However, we cannot rule out the possibility that the abnormal size of nuclei is a result of abnormal condensation of the DNA. We also produced string clones in the background of 31.6 kb rescue construct (Fig. 6A) and, as expected, observed mutant clones the size of sister clones and a comparable size of nuclei in each group.
These data suggest that Notch pathway activity will impinge in (6.4 kb region)-enhancer element. To test this, we crossed both the R6.4-lacZ and R4.9-lacZ gene fusions to the line mutant for Delta and analyzed the expression of these elements in egg chambers with germline mutant for Delta. In controls, the expression of R6.4 element was observed in stage 5 but not in stage 9 egg chambers (Fig. 7A-B). However, in Delta germ line clones, expression of R6.4 element was observed in domains of 5-20 cells through the follicle cell layer past stage 6 (Fig. 7C-D, n=36). By contrast, when R4.9-element was analyzed in Delta germ line clones, no expression beyond the normal early expression was observed (data not shown). These data suggest that Notch pathway activity does control String at the 6.4 kb element but not at the 4.9 kb element.
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DISCUSSION |
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Control of the mitotic to endocycle transition
Endocycles are widespread in plants and animals including humans and Drosophila. In human placenta, subgroups of trophoblast cells enter the endocycle and terminally differentiate to become trophoblast giant cells. It is known that over-proliferation of the trophoblast cells causes choriocarcinoma, placental cancer, but the signal that triggers the endocycle transition is not known. Another example of a mammalian cell type that becomes polyploid by endocycling is the megakaryocyte, a blood cell that is specialized to produce platelets (Zimmet and Ravid, 2000). These cells undergo endomitosis, and the transition from mitotic to endomitotic cycle is influenced by the secreted signal thrombopoietin. Thrombopoietin upregulates Cyclin D3 protein and Cyclin D3 overexpression has been found to increase megakaryocyte ploidy in transgenic mice (Zimmet et al., 1997). In addition, recent data has shown that constitutively active form of Notch can induce CycD expression and that CSL (stands for CBF1, Su(H), and Lag-1) binding site is identified in the CycD promoter (Ronchini and Capobianco, 2001).
In Drosophila, cells adopt the endocycle program during both embryonic and adult stages. Embryonic endocycling cells are found in the gut, fat body, malpighian tubules and salivary glands (Smith and Orr-Weaver, 1991), and in adult tissues, endoreplicating cells are found in the ovary (nurse cells and follicle cells) and in the wing (sensory neurons). The transition from mitotic to endocycle during embryogenesis coincides with transcriptional repression of the mitotic regulators Cdk1, Cyclin A, Cyclin B, Cyclin B3 and Cdc25/string (Sauer et al., 1995). Control of this transcriptional repression is not yet understood. In addition to transcriptional level control, embryonic cells control their mitotic machinery at the protein level to ensure the transition to endocycles (Sigrist and Lehner, 1997).
It is plausible that Notch also regulates other components of the cell cycle in addition to String, because the transition to the endocycle requires not only the repression of a mitosis promoter (string) but the upregulation during G2 of an S phase promoter, such as CycE and/or CycD (for comparison, during early embryogenesis cells that lack String pause in G2 rather than undergoing endocycles). However, when string was restored to clones under the control of the 15.3 kb rescue construct, which contains the control element active in the germarium and stage 1 but not the control element active between stage 3 and stage 6, some cell divisions occurred before premature stopping of the mitotic cycle, and interestingly, the nuclei were 2.2 fold bigger in the mutant clones than in the sister clones or in the neighboring wild type cells (Fig. 6G) suggesting that the mutant cells that stopped dividing too early also entered the endocycle too early. Thus, in contrast to embryonic cells, cessation of string expression may lead the follicle cells to endocycle rather than simply arrest, and thus Notch might act solely on string to stop mitosis and the subsequent transition to the endocycle could be due to other factors constitutively present in follicle cells. However, we cannot rule out the possibility that Notch also acts on other cell cycle components, and based on the example of megakaryocytes, in which thrombopoietin promotes the mitotic-endocycle switch and also elevates the levels of CyclinD, it will be interesting to examine the role of Cyclin D in the follicle cell transition.
Notch pathway controls cell division?
We have shown that in Drosophila follicle cells string mRNA expression coincides with the mitotic cycle of follicle cells. Furthermore, we have shown that two separate controlling elements are found in the promoter region of string for early follicle cell expression, one of which is shut off just at the mitotic cycle-endocycle transition and is likely to be the target of regulation by the Notch pathway. Previous work suggests that string transcription is altered in embryos mutant for axis, gap, pair rule, segment polarity, homeotic, neurogenic and proneural genes (Arora and Nüsslein-Volhard, 1992; Edgar et al., 1994), suggesting that the upstream regulatory elements of string is a sophisticated integrator of patterning signals. It will be interesting to determine how Su(H) functions to repress string expression and leads to the transition to the endocycle.
Germline follicle cell signaling
Signaling between the somatic follicle cells and the underlying germline plays a crucial role in coordinating the complex process of oogenesis. Previous work has shown important roles for epidermal growth factor receptor signaling from the oocyte to the follicle cells at two stages of oogenesis, and revealed that the follicle cells signal back to the oocyte to help define the oocyte anteroposterior axis later in oogenesis (Schupbach, 1987; Gonzalez-Reyes et al., 1995; Roth et al., 1995; Anderson, 1995; Ruohola et al., 1991; Deng and Ruohola-Baker, 2000; Ray and Schüpbach, 1996; Rongo and Lehmann, 1996). The new oocyte-germline signaling event from Delta in the germline to Notch in the surrounding follicle cells defined in this paper adds a new twist to our understanding of germline-follicle cell signaling during oogenesis and plays an important role in coordinating the division of follicle cells with crucial steps in the maturation of the oocyte. The next challenge in this area is to understand what regulates the key regulatory step in the process, the elevation of Delta protein level in the germline.
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ACKNOWLEDGMENTS |
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