Gene name - stem cell tumor/rhomboid-2
Synonyms - brother of rhomboid
Cytological map position - 62A1
Function - enzyme
Keywords - oogenesis, A/P axis formation, spermatogenesis, EGF receptor signaling pathway
Symbol - stet/rho-2
FlyBase ID: FBgn0041725
Genetic map position -
Classification - serine-type peptidase
Cellular location - integral membrane protein
The Drosophila rhomboid (rho) gene participates in localized activation of EGF-receptor signaling in various developmental settings. The Rhomboid protein has been proposed to promote presentation and/or processing of the membrane-bound Spitz (mSpi) EGF-related ligand to generate an active diffusible form of the ligand. The rhomboid-related gene, variously known as stem cell tumor (stet), brother of rhomboid (brho) and rhomboid-2 (rho-2), was first identified as a gene involved in the determination of germ line cell fate. Later, sequence similarity searches identified stet/brho/rho-2 as a rhomboid related gene. In contrast to rho, which is expressed in complex patterns during many stages of development, stet/brho/rho-2 appears to be expressed only in germ cells. brho transcripts are present in early oocytes and abut posterior follicle cells which exhibit high levels of MAPK activation. brho, like rho, collaborates with Star to promote signaling through the Egfr/Mapk pathway, and genetic evidence indicates that Brho can activate both the mSpi and the Grk precursor EGF ligands in the wing. It is proposed that endogenous brho may activate the oocyte-specific Gurken ligand and thereby participate in defining posterior cell fates in the early follicular epithelium (Guichard, 2000; Schulz, 2002).
Interactions between germ cells and somatic support cells in Drosophila depend on wild-type function of the stet gene. In males, stet acts in germ cells to allow their encapsulation by somatic cyst cells and is required for germ cell differentiation. In females, stet function allows inner sheath cells to enclose early germ cells correctly at the tip of the germarium. The stet mutant phenotype suggests that stet facilitates signaling from germ cells to the epidermal growth factor receptor on somatic cells, resulting in the encapsulation of germ cells by somatic support cells. The micro-environment provided by the surrounding somatic cells may, in turn, regulate differentiation of the germ cells they enclose (Schulz, 2002).
Germ cells normally differentiate while in intimate contact with somatic support cells. In mammals, differentiating male germ cells are enclosed in somatically derived Sertoli cells and oocytes are surrounded by somatic granulosa cells. In both cases, interactions between germ cells and surrounding somatic cells play important roles in gametogenesis. Similarly, in Caenorhabditis elegans, early germ cells are closely associated with the somatic distal tip cell, which provides crucial signals that govern germ cell proliferation versus differentiation. At subsequent stages, C. elegans germ cells interact with somatic sheath and spermathecal cells. In insects as well, germ cells are closely associated with somatic cells, which play key regulatory roles in germ cell fate (Schulz, 2002 and references therein).
In Drosophila males, germline stem cells lie at the apical tip of the testis, in intimate contact with somatic hub and cyst progenitor cells. Upon stem cell division, the daughter cell displaced away from the hub becomes encapsulated by two somatic cyst cells and initiates differentiation. The surrounding somatic cyst cells play an important role in the initiation of germ cell differentiation, and later in the transition from mitosis to meiosis. In Drosophila females, somatic cells at the apical tip of the germarium form a specialized niche in which germline stem cells are maintained through signaling from the soma. After mitotic amplification, clusters of 16 interconnected female germ cells become surrounded by follicle cells, which form an epithelial sheath around each developing egg chamber. Interactions between germ cells and follicle cells regulate such critical events as egg chamber formation and determination of the polarity of the developing oocyte (Schulz, 2002 and references therein).
Signaling via the Epidermal growth factor receptor (Egfr) mediates many cell-cell interactions where one cell influences the proliferation or differentiation of a closely apposed partner. Despite the exquisitely localized and temporally specific requirements for Egfr activation in normal development documented in Drosophila, the Egfr and its major ligand spitz (spi) are widely expressed. Spatial and temporal control of Egfr pathway activation appear to be achieved at the level of ligand activation. spi is synthesized as a transmembrane protein. Proteolytic cleavage of spi by the transmembrane protein Rhomboid (Rho) within the Golgi apparatus of the signal sending cell produces a potent diffusible ligand. Expression of rho is spatially and temporally controlled, providing developmental specificity to activation of the Egfr pathway (Schulz, 2002 and references therein).
In Drosophila oogenesis, germ cells signal via the germline Egfr ligand gurken (grk) to specify the correct behavior of follicle cells in encapsulating each individual cluster of 16 germ cells, and later to pattern the follicle cell layer. So far it has been unclear how Egfr is activated during oogenesis. Germline clones mutant for rho produce wild-type eggs, suggesting that rho is not required in germ cells. Instead, rho is expressed in follicle cells depending on Egfr activation, most likely to spread and amplify the initial signaling event (Schulz, 2002).
stet plays a crucial role in signaling from germ cells to somatic cells. Wild-type function of stet is required for encapsulation of germline stem cells and their progeny by somatic support cells and germ cell differentiation in both Drosophila males and females. Clonal analysis and rescue experiments in testes have demonstrated that stet function is required in germ cells. The conserved protease motif in the Stet protein and its subcellular localization (Ghiglione, 2002) suggest that stet functions through the same biochemical mechanism as rho. In support of this, expression of rho in germ cells rescues the stet mutant testes phenotype. It is proposed that stet activates signaling from germ cells to the Egfr on somatic support cells to set up the crucial associations between germ cells and soma that are required for normal gamete differentiation (Schulz, 2002).
Wild-type function of the stet locus is required for male germ cells to proceed through early stages of differentiation. Loss-of-function stet mutant males were viable but sterile. Adult stet mutant males had tiny testes filled with small cells resembling cells normally found only at the tip of wild-type testis. Early male germ cells fail to differentiate and instead accumulate in third instar larval testes from loss-of-function stet animals, based on appearance in phase contrast and DIC microscopy, nuclear size in DAPI-stained preparations and expression of cell-type specific markers. In wild type, early germ cells (stem cells, gonialblasts and spermatogonia) are located at the apical tip of the testis and express the lacZ enhancer trap marker S3-46. Spermatocytes are located more distally, fill most of the larval testis and do not express the S3-46 enhancer trap marker. Larval testes from stet mutant males are filled with cells expressing ß-galactosidase from the S3-46 marker, suggesting that they are early germ cells (Schulz, 2002).
In wild-type testes, mitotically active early germ cells are observed exclusively at the apical tip upon staining with anti-phosphorylated Histone-H3 antibody. Germline stem cells and gonialblasts divide as single cells, while spermatogonia divide in groups of two, four or eight cells. In stet mutants, many phosphorylated Histone-H3-positive cells are scattered throughout the testes, suggesting that the early germ cells accumulating in stet mutant testes remain mitotically active. Many anti-phosphorylated Histone-H3-positive cells are detected as single cells throughout stet mutant testes, indicating that cells with stem cell or gonialblast identity have been displaced away from the tip (Schulz, 2002).
stet mutant testes appear to contain a mixture of germ cells with stem cell, gonialblast and spermatogonial identities. In wild-type testes, alpha-spectrin is localized to a ball-shaped spectrosome in germline stem cells and gonialblasts and to the branched fusome structure passing through the intercellular bridges between spermatogonia. In wild-type testes, 10 to 20 cells with a spectrosome dot can be detected at the apical tip. In stet mutant testes, 20 to 40 cells with spectrosome dots are detected at the apical tip, and many cells with a spectrosome dot displace away from the tip, suggesting an increased number of stem cells and/or gonialblasts. However, most of the small germ cells accumulating in stet mutant testes are interconnected by short, branched fusomes, suggesting spermatogonial identity (Schulz, 2002).
Staining for escargot (esg) mRNA also suggested an increased number of cells with stem cell characteristics. In wild-type, esg mRNA is detected in the somatic hub cells and in the five to nine germline stem cells around the hub, but not in gonialblasts and spermatogonia. stet mutant testes had in average 40 esg-positive cells, ranging from the normal five to more than 100, with some at the apical tip and some displaced away from the apical tip (Schulz, 2002).
Staining for somatic hub cell lacZ enhancer trap markers (254, S2-11) or the hub cell surface marker Fasciclin III (FasIII) revealed that somatic hub cells are present at the apical tips of stet third instar larval testes. However, the hub often appeared slightly enlarged and less tightly packed than in wild type, much as in agametic testes from sons of oskar mutant mothers (Schulz, 2002).
In wild-type testes, somatic cyst progenitor cells act as stem cells for the cyst cell lineage and lie next to the hub adjacent to germ line stem cells. The cyst progenitor cells produce somatic cyst cells, two of which encapsulate each gonialblast and its progeny throughout all subsequent stages of male germ cell differentiation. Somatic cyst cells and cyst progenitor cells are present in loss-of-function stet mutant testes based on the presence of traffic jam (tj) protein, a transcription factor detected in nuclei of cyst progenitors and early somatic cyst cells in wild-type. The number of Tj-positive somatic cyst cell nuclei detected in stet mutant testes varies, ranging from 20 to 90, compared with 70 to 80 Tj-positive somatic cyst cell nuclei detected in wild-type testes. Somatic cyst cells are also detected in stet mutant testes by several nuclear targeted lacZ enhancer-trap markers (11, 600, 473) (Schulz, 2002).
Despite the presence of somatic cyst cell nuclei, cyst cells did not appear to envelop germ cells in stet mutant testes. In wild type, somatic cyst progenitors and cyst cells surround early germ cells in a net-like pattern that can be visualized using cytoplasmic cyst cell markers. In wild-type testes, ß-galactosidase activity encoded by the 17-en-40 insert (wingless-lacZ enhancer trap marker) is detectable throughout the cell body and cytoplasmic extensions of somatic cyst cells as they surround the developing germ cells. In stet mutant testes stained for the same cytoplasmic cyst cell marker, cyst cells appear round, with a small percent (10%-30%) having detectable short cytoplasmic extensions. Similar results were obtained by expressing a cytoplasmic UAS-GFP under the control of the patched-GAL4 (ptc-GAL4) transcriptional activator. In wild-type testes, the GFP-positive cytoplasm of somatic cyst cells forms a net-like pattern surrounding the germ cells. In contrast, in stet mutant testes, cyst cells are mostly detected as round GFP-positive structures, and only a few GFP-positive cytoplasmic extensions are observed. The number of somatic cyst cells in stet mutant testes detected with cytoplasmic markers (ranging from seven to 46) was lower than the number of cyst cells (20 to 90) detected with the nuclear marker Tj (Schulz, 2002).
Analysis of male germline clones indicates that stet function is required in germ cells. Clones of cells that lack the stet gene were generated in stet/+ animals using a FRT/FLP recombination system and identified by lack of expression of a nuclear targeted GFP. GFP was expressed under control of the ubiquitin promotor, allowing for detection of both the round nuclei of germ cells and the triangular shaped nuclei of somatic cells. Control clones wild-type for stet produced clusters of GFP-negative germ cells that developed normally into spermatocytes, based on appearance by phase contrast microscopy and nuclear size when stained with DAPI. In contrast, stet/stet mutant germ cells did not differentiate into spermatocytes. Instead, germline clones produced large clusters of GFP-negative cells resembling early germ cells, based on appearance by phase contrast microscopy and by their small, bright nuclei when stained with DAPI. The cells in stet mutant clones express piwi mRNA and other early germ cell markers normally restricted to the anterior tip of the testis. Staining with esg mRNA and alpha-spectrin revealed that the cells within individual stet mutant clones are a mixed population resembling stem cells, gonialblasts and spermatogonia, much as the germ cells accumulating in testes from stet homozygous mutant males (Schulz, 2002).
Loss of stet function in the germline affects association with the stet/+ heterozygous somatic cyst cells. Most stet mutant germ cell clones are not associated with the two accompanying somatic cyst cells (Schulz, 2002).
The identity of stet was confirmed by rescue experiments. Consistent with stet function in germ cells, expression of a UAS-stet-cDNA in germ cells of stet mutant testes under control of the germ cell-specific driver nanos-GAL4-VP16 restores spermatogenesis. Since expression with the UAS-GAL4 system is temperature dependent, rescue was not always complete and occasionally clusters of stet mutant germ cells were detected in the testes. In contrast, expression of UAS-stet under control of the somatic cell driver ptc-GAL4 did not rescue the stet mutant phenotype, suggesting that stet function in germ cells is both required and sufficient to allow germ cell differentiation (Schulz, 2002).
Expression of rho in germ cells of stet mutant testes also restores spermatogenesis, indicating that stet and rho may function through the same biochemical mechanism. To explore how stet function in early male germ cells might relate to the Egfr signal transduction pathway, the expression and effects of other components of the pathway on early male germ cell differentiation were tested. Expression of secreted forms of the Egfr ligands spi and grk in male germ cells under the control of the nos-GAL4 activator did not modify the stet mutant phenotype, raising the possibility that another ligand may play a role in male germ cells. rho normally acts synergistically with the transmembrane protein Star within the signaling cell to activate spi. In situ hybridization with a Star mRNA probe to wild-type testes revealed high levels of Star expression at the apical tip (Schulz, 2002).
Consistent with a potential role for the Egfr in somatic cells, activated MAP-kinase is detectable in somatic cyst cells of wild-type testes. In stet mutant testes, MAP-kinase expression is restricted to the somatic hub cells and a few (two to five) cells next to the somatic hub in the position corresponding to that of cyst progenitor cells. Although cyst cells were present in stet mutant testes, no activated MAP-kinase was detected in cyst cells displaced away from the hub. Likewise, activated MAP-kinase is detected in the cytoplasmic extensions of inner sheath cells of wild-type germaria, but only in a few inner sheath cells in germaria from stet mutant females (Schulz, 2002).
It is concluded that the stet gene plays a crucial role in germ cell differentiation in both males and females. In animals that lack stet function, somatic support cells fail to surround germ cells properly and germ cells accumulate at early stages of differentiation. Mosaic analysis in testes suggested that stet function is required in germ cells for normal association between early germ cells and somatic cyst cells. This, along with the molecular identity of the stet gene, suggests that stet activates signaling from germ cells to the soma to allow normal interactions between germ cells and somatic support cells (Schulz, 2002).
The stet gene encodes a homolog of rho, which plays an essential role in Egfr signaling. Rho has been shown to localize to the Golgi apparatus, where it acts as a protease to cleave the Egfr ligand spi. The stet protein also localizes to the Golgi apparatus in cell culture experiments (Ghiglione, 2002), and contains the protease motif described for Rho. Consistent with the idea that stet may encode a protease, three strong stet alleles alter residues in the conserved protease domain (Schulz, 2002).
Mosaic analysis and rescue experiments showed that stet function is required in male germ cells for normal germ cell differentiation. The possibility that this is a cell-autonomous function of stet within the germ cells cannot be excluded. However, members of the rho family of proteins have been shown to play roles in the production of signals sent to neighboring cells, and do not seem to be directly required for differentiation of the ligand producing cell itself. Therefore the idea that stet functions primarily by activating signaling from germ cells to somatic cells is favored. It is proposed that once proper contacts between germ cells and somatic cells are established, signals from somatic cells then regulate germ cell differentiation. It is hypothesized that germ cells in stet mutants fail to differentiate because they lack the somatic micro-environment that provides essential cues regulating germ cell differentiation (Schulz, 2002).
Experiments in wing discs demonstrate that stet is able to collaborate with Star to promote signaling through the Egfr/MAP-kinase pathway. stet can activate the Egfr ligands spi and grk when ectopically expressed in wing discs or follicle cells (Guichard, 2000; Ghiglione, 2002). Expression of rho in germ cells can substitute for stet function, and Star is expressed at the tip of wild-type testes. In addition, in stet mutant testes most somatic cyst cells fail to express activated MAP-kinase, the downstream indicator for Egfr signaling. Based on these observations, it is proposed that the stet gene functions as an activator of signaling from early germ cells to the Egfr presented on the surface of somatic cells and that activation of the Egfr in somatic cells is required to establish normal interactions between germ cells and somatic cells (Schulz, 2002).
Testes from animals carrying a temperature-sensitive allele of the Egfr show accumulation of germ cells that appeared to be stem cells, gonialblasts and spermatogonia. This similarity to the stet mutant phenotype in testes is consistent with stet and the Egfr functioning in the same pathway. However, the Egfrts mutant phenotype in testes does not exactly resemble the stet mutant phenotype. In stet mutant testes, somatic cyst cells do not envelope clusters of early germ cells properly. Testes from Egfrts mutant animals display many defects in the association of somatic cyst cells and early germ cells, including some cases in which germ cell clusters were associated with multiple somatic cyst cells. Since analysis of the Egfrts phenotype was performed after a temperature shift, it is hypothesized that testes from Egfrts animals may have had sufficient residual Egfr activity to allow some and possibly abnormal association of early germ cells and somatic cyst cells. In addition, the Egfrts mutant may not be null for Egfr function at 29°C, the temperature assayed. Consistent with this likely possibility, no cyst cell clones mutant for Egfr null alleles have not been recovered, even though somatic cyst cells are detected in the Egfrts allele (Kiger, 2000). In contrast, in this study, the phenotype of animals null mutant for stet throughout development was reported (Schulz, 2002).
stet may activate a yet unidentified Egfr ligand to recruit somatic cells for germ cell encapsulation. Even though stet can activate spi and grk when ectopically co-expressed in wing discs (Guichard, 2000), expression of secreted forms of spi or grk in male germ cells did not rescue the stet mutant phenotype in this study. Loss-of-function alleles of grk that cause severe defects in female gametogenesis do not show an early germ cell over-proliferation phenotype in testes, suggesting that stet does not function through grk activation. In females, eggs laid by stet mutant mothers do not display the grk or spi mutant phenotypes, but instead, they either show a variety of defects or develop into phenotypically normal adults. Further investigation of the Egfr signal transduction pathway remains to be undertaken to identify additional components of the pathway and test their potential role in interactions between early germ cells and surrounding somatic cells (Schulz, 2002).
The early stages of gametogenesis in Drosophila are strikingly similar in males and females: in both sexes, germ cells are in constant contact with encapsulating somatic cells. Based on ultrastructural studies by electron microscopy and light microscopy analysis using several markers, the inner sheath cells in region 1 and 2A of the germarium appear to form cytoplasmic extensions that contact female germ line stem cells, cystoblasts and cystocytes. This study provides the first insight into the function of the inner sheath cells. In stet mutant females, the cytoplasmic extensions from the inner sheath cells fail to surround the germ cells and the germ cells fail to progress to the cystocyte stages. It is proposed that the inner sheath cells at the tip of the germarium may play a role similar to the somatic cyst cells surrounding germ cells in testes, providing a microenvironment that directs female germ cell differentiation (Schulz, 2002).
The data predict a new function for the Egfr signaling pathway in the female gonad. Egfr signaling, activated by stet, may be required to set up the normal interactions of early female germ cells and somatic inner sheath cells in region 1 and 2A of the germarium. No accumulation of early germ cells with cytoplasmic Sxl protein and spectrosomes was observed at the tip of the germarium after shifting animals carrying the Egfrts allele to the restrictive temperature as adults. However, many ovarioles from females carrying Egfrts alleles also did not display defects at later stages of oogenesis in these experiments, again indicating that the Egfrts allele has residual Egfr activity and may not reflect the Egfr loss-of-function situation (Schulz, 2002).
The possibility that stet activates other signaling pathways to set up proper physical interactions between germ cells and somatic support cells cannot be ruled out. In females, normal encapsulation of germ cells by somatic follicle cells requires the neurogenic genes brainiac (brn) and egghead (egh). brn encodes a secreted protein and egh encodes a secreted or transmembrane protein. Double mutant combinations of grk and brn display much stronger defects in encapsulation of germ cells than either grk or brn mutants alone, suggesting that the brn and egh pathway and the Egfr pathway function partially redundantly in formation of the prefollicular epithelium. This opens the possibility that encapsulation of early female germ cells by inner sheath cells and encapsulation of male germ cells by somatic cyst cells depend on another signaling pathway instead of, or in addition to, the Egfr signal transduction pathway (Schulz, 2002).
For information on stet/rho-2 evolutionary homologs see rhomboid.
Six sequences from the Berkeley Drosophila Genome Project database were identified that exhibit high similarity to rhomboid. These include rhomboid-2 (CG12083), rhomboid-3 (CG1214) and rhomboid-4. Both rhomboid-2 and rhomboid-3 are cytologically located very close to the rhomboid-1 (rhomboid) gene on the third chromosome, whereas rhomboid-4 (CG1697) has been mapped to position 10C on the X chromosome by polytene chromosome in situ hybridization. Full length cDNAs were isolated for each of the new genes and their sequences were compared. The most highly conserved region spans the seven transmembrane domains; the hydrophilic amino terminus is strikingly divergent. This pattern of similarity is very like that between Drosophila rhomboid-1 and its recently identified mammalian homologs (Pascall, 1998), and suggests that the transmembrane domains provide a core function for Rhomboid-like proteins. A phylogenetic tree derived from these sequences indicates that rhomboid-3 is most closely related to rhomboid-1, followed by rhomboid-2; rhomboid-4 is the least related. The amino-terminal region of Rhomboid-4 contains two tandemly arranged EF-hand motifs that are putative calcium-binding domains. There are three further rhomboid-like genes predicted (rhomboid-5, rhomboid-6, and rhomboid-7). Rhomboid-5 (CG5364) is located at 31C; Rhomboid-6 (CG17212) at 33C, and Rhomboid-7 (CG8972) at 48E. The most conserved region encompasses the transmembrane domains, while diverging in the hydrophilic amino termini. This striking conservation of rhomboid-like genes suggests that the primordial function of these proteins is a fundamental cellular process. The restriction of Drosophila Rhomboid-1 and Rhomboid-3 function to Egfr signaling presumably represents a specialization of this original function (Wasserman, 2000).
Like rho, brho/stet is predicted to encode a protein with seven transmembrane (TM) domains, with generally very short stretches of hydrophilic amino acids between the TM domains and a longer loop between TM1 and TM2. Comparison of the two proteins reveals that the strongest identities fall within the transmembrane domains. Rho and Brho are 41% identical and 64% similar overall and 62% identical and 83% similar within the transmembrane domains. This higher degree of conservation in predicted TM domains has also been observed for rhomboid-related genes found in the nematode, rat, human, plants, yeast, and bacteria. In addition to the TM domains, a stretch of 25 amino acids located at the end of the first loop between TM1 and TM2 is also very highly conserved. In contrast, the hydrophilic termini of the Rho and Brho proteins do not show any significant sequence similarity. Moreover, the N-terminal portion of brho is much shorter than that of rho. Some of the rho-like genes found in more distant organisms like plants, yeast, and bacteria have fewer or more predicted transmembrane domains. The most highly conserved regions in the Rhomboid family of proteins are the first loop between TM1 and TM2 and the TM2-TM6 transmembrane domains (Guichard, 2000).
A phylogenic tree assembled from known Rho-related proteins closely follows the ancestral relationships between organisms. This cladistic analysis reveals that gene duplications giving rise to new Rho proteins have occurred at different taxonomic levels. In the case of Drosophila rhomboid-related genes, there is clear evidence for several distinct rounds of gene duplication events that gave rise to the Drosophila Rho-related genes. The rho-related [10C6], rho-related [31D10], and rho-related [33C1] genes clearly arose before the divergence of arthropods and vertebrate lineages, whereas duplications that gave rise to the cluster consisting of rho, brho, and rho-related [62A1] evidently took place sometime after the divergence of the ecdysozoa and the lophotrochozoa (Guichard, 2000).
To explore the mechanism of action of stet, the stet gene product was identified by positional cloning. The stet gene was mapped to cytological region 62A1 by recombination analysis and deficiency complementation. The stet mutation was uncovered by Df(3L)PX62, which removes ~60 kb of genomic DNA in 62A1. Analysis of the genome sequence in this region revealed 12 potential transcription units (Schulz, 2002).
Sequence analysis of genomic DNA from several EMS induced stet alleles identified stet as a predicted seven transmembrane protein. The predicted stet protein shows high sequence similarity to the Drosophila rho protein and had been published under the names CT5484 and rhomboid-2 (Wasserman, 2000) and brother of rhomboid (brho; Guichard, 2000). The stet gene product will be referred to as stet based on naming genes by the mutant phenotype. Two strong stet alleles introduced stop codons in the stet protein-coding region, truncating the predicted protein. Another strong stet allele introduced a splice site change resulting in a frame shift that led to a premature stop codon in the predicted stet protein. Several other EMS alleles altered conserved amino acids in the predicted stet transmembrane domains; stet 8A, stet 3 and stet z30369 had amino acid replacements in the conserved protease motif. Comparison of the genomic sequence with several independent cDNAs isolated from a testes cDNA library revealed that the stet testis transcript contained four exons. The predicted protein from the stet testes cDNA has stop codons in all three reading frames upstream of the predicted initial methionine, located in exon 2 (Schulz, 2002).
date revised: 22 December 2002
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