Wnt oncogene analog 2: Biological Overview | Evolutionary Homologs | Developmental Biology | Effects of Mutation | References

Gene name - Wnt oncogene analog 2

Synonyms - DWnt-2

Cytological map position - 45E1--45E4

Function - ligand

Keywords - segment polarity, gonads, spermatogenesis

Symbol - Wnt2

FlyBase ID:FBgn0004360

Genetic map position - 2-[59]

Classification - Wnt family

Cellular location - secreted



NCBI links: Precomputed BLAST | Entrez Gene
BIOLOGICAL OVERVIEW

Recent literature
Wang, S., Gao, Y., Song, X., Ma, X., Zhu, X., Mao, Y., Yang, Z., Ni, J., Li, H., Malanowski, K.E., Anoja, P., Park, J., Haug, J. and Xie, T. (2015). Wnt signaling-mediated redox regulation maintains the germ line stem cell differentiation niche. Elife 4. PubMed ID: 26452202
Summary:
Adult stem cells continuously undergo self-renewal and generate differentiated cells. In the Drosophila ovary, two separate niches control germ line stem cell (GSC) self-renewal and differentiation processes. Compared to the self-renewing niche, relatively little is known about the maintenance and function of the differentiation niche. This study shows that the cellular redox state regulated by Wnt signaling is critical for the maintenance and function of the differentiation niche to promote GSC progeny differentiation. Defective Wnt signaling causes the loss of the differentiation niche and the upregulated BMP signaling in differentiated GSC progeny, thereby disrupting germ cell differentiation. Mechanistically, Wnt signaling controls the expression of multiple glutathione-S-transferase family genes and the cellular redox state. Finally, Wnt2 and Wnt4 function redundantly to maintain active Wnt signaling in the differentiation niche. Therefore, this study reveals a novel strategy for Wnt signaling in regulating the cellular redox state and maintaining the differentiation niche.

During pupal development, two separate tissues, the gonad and the genital disc, must grow toward each other, recognize, and fuse with one another. In the male, the gonads differentiate to form the testes and the genital disc differentiates to form the external genitalia and the internal structures that connect to the testes. The sheath of the male reproductive tract develops from two populations of cells: the pigment cells (cells of somatic origin associated with the gonad) and the somatically derived precursors of smooth muscle cells. These cells migrate to form a bilayered sheath that covers both the mature gonad (the testis) and a portion of the genital disc (the seminal vesicle). Organogenesis of the male reproductive tract sheath depends on the proper specification and migration of cells; such processes may require either intrinsic cues or extracellular signals (Kozopas, 1998).

The existence of signaling molecules necessary for the development of the male reproductive tract was first postulated more than 60 years ago when researchers were studying two aspects of development: the morphogenesis of the testis and the sex-specific presence of testis pigment cells. It was noted that the male gonads of gynandromorphs, or sexual mosaics, which do not possess a male genital disc, fail to undergo morphogenesis from an ovoid to a spiral shape (Dobzhansky, 1931). In transplantation experiments, it was found that male gonads only undergo morphogenesis when attached to a male genital disc and that the extent of spiraling, a species-specific trait, depends on the species of the genital disc (Stern, 1941a and b). These results led to the hypothesis that the male genital disc releases a signal, an inducer of morphogenesis, to which the gonad responds (Kozopas, 1998).

A second signal was proposed to explain the fact that a certain male-specific cell type can be induced in females. In gynandromorphs that contain ovaries and a male genital disc, some male-specific pigment cells are often present. Through transplantation experiments, it was determined that these cells normally derive from the male gonad, which raised the question of whether the female gonad is the source of the pigment cells seen in gynandromorphs. This appears to be the case, as transplanting a male genital disc into a female is sufficient for some cells of the ovary to acquire a pigment cell fate. Clearly, some signal emanating from male tissue can support the differentiation of female cells into male testis pigment cells. For many years, these signals, crucial effectors of male development in the reproductive tract, were left unpursued (Kozopas, 1998 and references).

In a screen for mutations in Wnt2, a member of the Wnt family of genes (Russell, 1992), Wnt2 was found to be required for the development of the sheath of the male reproductive tract and testis morphogenesis. Wnt2 is expressed in somatic cell precursors. When Wnt2 is expressed ectopically in females, male-specific pigment cells appear. Pigment cells, the outer cells of the testis sheath, are absent in null mutants, indicating that Wnt2 is required for pigment cell specification in males. The inner muscle layer of the testis sheath fails to develop in the male mutants and the testis does not undergo its normal morphogenesis (Kozopas, 1998).

This raises two questions: (1) How is it possible to demonstrate Wnt2 involvement in muscle cell determination and pigment cell origin? (2) How does the somatically derived muscle layer come to lie inside the gonad derived pigment layer?

(1) The involvement of Wnt2 in pigment cell origin was proven by overexpression experiments. The pigment cells are a sexually dimorphic cell type found only in the male. The finding that Wnt2 is expressed only in the male third instar larval genital disc suggested that Wnt2 is the signal provided by a transplanted male genital disc to induce pigment cell fate in females. To test this hypothesis, Wnt2 was expressed ectopically in clones during female development. When clones were induced in third instar female larvae, all of the resulting adults had ectopic pigment cells, as assessed by their production of yellow pigment (Kozopas, 1998).

(2) To understand the role of Wnt2in the formation of a complete muscle layer, the development of this tissue was examined in wild-type animals during pupation. The muscle precursor cells have a somatic origin in the male genital disc. Muscle precursors express twist. Expression of Twist is initiated in the mesoderm during embryogenesis, persists in adult muscle precursors, and is required at high levels for myogenesis. Because the muscle precursors must migrate from the genital imaginal disc to form the testis sheath, the muscle phenotype in mutant adults indicates a thwarted attempt at the normal developmental process. The myoblasts in Wnt2 mutants begin migration over the testis, but fail to complete it. The lack of pigment cells in adult mutants, however, could indicate that either these cells are not specified or they degenerate for lack of contact with a normal muscle layer. To address this, the expression of a pigment cell marker was examined in Wnt2 mutant gonads before any contact of the gonad with the muscle precursor cells from the genital disc had been established. At 24 hr after puparium formation, 6 hr before the genital disc could be expected to contact the gonad, mutants already lack the pigment cell layer that covers the wild-type gonad. Even at the late third instar larval stage, the earliest that expression can be detected from the pigment cell marker line, the mutants lack pigment cells. Thus it appears that the pigment cells are never specified in the mutants or die before the morphogenesis of the reproductive tract occurs. It is concluded that there is a dual defect in Wnt2 mutants: failure of muscle precursor migration and failure in pigment cell specification (Kozopas, 1998).

The role of Wnt2 in testis muscle cell development, as revealed by the mutant phenotype, is to ensure the proper morphogenesis of the muscle precursor cells. Instead of initiating cell differentiation, Wnt2 contributes either to the migration of the muscle precursors away from the genital disc or to their adherence and migration over the testis. This contribution may be a direct one, in which Wnt2 regulates motility or adherence, or an indirect one, in which the role of Wnt2 is to specify the pigment cell substrate. Wnt2 activity is required in males for the presence of pigment cells. Wnt2 is necessary and sufficient for the differentiation of the male-specific pigment cell fate, at least for a certain population of cells. These experiments were not able to clarify what female cell type gives rise to the pigment-producing cells. These cells may derive from the colorless sheath cells of the ovary or an external cell type of the ovary, referred to as a lamellocyte and seen only in prepupae. This may be the cell type with the potential to become a pigment cell (Kozapas, 1998).

In summary, Wnt2 expression in males is required for testis pigment cells. Ectopic expression of Wnt2 is sufficient for the formation of ectopic pigment cells in females. Wnt-2 is also required for the normal development of the testis muscle, although it is not known if this requirement is direct. The pigment cells appear to be the substrate under which the myoblasts must migrate, and their absence in the Wnt2 mutant may explain the observed abnormal muscle formation. However, Wnt2 expression at the precise time and location of myoblast migration suggests that Wnt2 could have an independent function in the migration process. Currently, no experiments have been carried out to distinguish between a direct and indirect role for Wnt-2 in testis muscle development (Kozopas, 1998).

Direct flight muscles depend on DWnt-2 for their correct patterning

The direct flight muscles (DFMs) of Drosophila allow for the fine control of wing position necessary for flight. In Wnt-2 mutant flies, certain DFMs are either missing or fail to attach to the correct epithelial sites. Using a temperature-sensitive allele, it has been shown that Wnt-2 activity is required only during pupation for correct DFM patterning. Wnt-2 is expressed in the epithelium of the wing hinge primordium during pupation. This expression is in the vicinity of the developing DFMs, as revealed by expression of the muscle founder cell-specific gene dumbfounded in DFM precursors. The observation that a gene necessary for embryonic founder cell function is expressed in the DFM precursors suggests that these cells may have a similar founder cell role. Although the expression pattern of Wnt-2 suggests that it could influence epithelial cells to differentiate into attachment sites for muscle, the expression of stripe, a transcription factor necessary for epithelial cells to adopt an attachment cell fate, is unaltered in the mutant. Ectopic expression of Wnt-2 in the wing hinge during pupation can also create defects in muscle patterning without alterations in stripe expression. It is concluded that Wnt-2 promotes the correct patterning of DFMs through a mechanism that is independent of the attachment site differentiation initiated by stripe (Kozopas, 2002).

The flight muscles develop from the myoblasts that adhere closely to the imaginal discs during larval development, then migrate and fuse to form syncytial tissue during pupation. The DFMs are tubular muscles that insert on apodemes, projections of the cuticle at the base of the wing hinge. Apodemes initially form during pupation as invaginations of the epithelium in the wing hinge primordium, before cuticle is secreted. Several of these apodemes correspond with internal portions of the axillary sclerites (small exoskeletal plates in the hinge). The most prominent group of DFMs are the muscles with obvious defects in the Wnt-2 mutant (Kozopas, 2002).

Null mutations in the Wnt-2 gene give rise to adult flies that cannot fly; they hold their wings out at an abnormal 45-90° angle from their body. In sections of thoraxes from null mutant flies, the IFMs appeared normal. However, in mutant flies dissected to directly examine the DFMs, it was found that particular DFMs are either attached inappropriately to the epidermis or they are absent. Although the extent of the muscle defects is variable, all flies exhibit some DFM defects. Most frequently affected are muscles 52 and 54. Muscle 52 is very often misattached such that its ventral edge inserts on the apodeme normally shared by muscles 49 and 50. In only 13% of hemithoraxes examined is muscle 52 present in its normal location, and in these flies, it is much reduced in size. A normal muscle 54 is only seen in 6% of the specimens. The finding that the Wnt-2 mutant has a frequent absence of muscle 54 and manifests a held-out wing position supports the conclusion from electrophysiological studies that this particular muscle functions in wing retraction at rest. The apparent absence of this muscle in the Wnt-2 mutants may be due to its misattachment in such a way that makes it unidentifiable, since ectopic muscle tissue is seen in more than half of the mutants. This ectopic muscle tissue either attaches to a known muscle site or appears to be unattached, but in no case does it misattach to a novel site on the epidermis (Kozopas, 2002).

Using a temperature-sensitive allele of Wnt-2, it has been determined that Wnt-2 function is required only during pupation for proper DFM development. The allele Wnt-2RJ, which was originally reported as a hypomorph for the phenotype of testicular pigment cell loss, is temperature-sensitive. When flies of the genotype Wnt-2RJ/Df are raised at 29°C, the mutants are flightless due to the absence of muscle 54. This DFM phenotype is hypomorphic because these flies rarely show the defects in the attachment of muscle 52 that are seen in the null mutants, although this muscle is usually smaller than in wild type. When Wnt-2RJ/Df flies are raised at 18°C, they are able to fly and display no DFM defects. When flies of this genotype are raised at 29°C until the white prepupal stage and are then shifted to 18°C, they also have normal DFMs. When the converse experiment is done and Wnt-2RJ/Df flies are raised at 18°C before shifting to the nonpermissive temperature at the white prepupal stage, flies display held-out wings and are flightless. Their phenotype is the same as flies raised at a constant 29°C, including the absence of muscle 54 (Kozopas, 2002).

To understand how Wnt-2 gene activity affects DFM development, a characterization of normal DFM development was undertaken. A marker was sought that would identify the DFMs during their development. ß-galactosidase expression was examined from the rP298 enhancer trap, which is an insertion in the embryonic muscle founder-specific gene dumbfounded (duf, also known as kirre). duf is an immunoglobulin superfamily member required for the aggregation and fusion of founder cells with naive myoblasts. In a newly formed puparium, duf-lacZ is expressed in only a subset of the adepithelial cells that are associated with the wing disc. It is expressed in cells at the ventral edge of the field of adepithelial cells that are in closest contact with the epithelium (Kozopas, 2002 and references therein).

Morphogenic movements of the wing disc during the first 6 h of pupation result in a three-dimensional structure in which the duf-lacZ-expressing cells reside on the inner face of the dorsal notum, directly adjacent to the wing hinge primordium. As pupation proceeds, the distance between the dorsal notum and the ventral pleura progressively decreases due to wing hinge morphogenesis. duf-lacZ- expressing cells will then migrate to additional sites on the inner face of the ventral pleura, reaching their destinations by 35 h after pupal formation (APF). At this time, it is apparent that duf-lacZ-expressing cells are present as clusters of cells. Myoblasts that do not express duf-lacZ can be seen aggregating with the myotubes formed from duf-lacZ-expressing cells. These observations, and the selective requirement of duf in embryonic muscle founders for fusion with myoblasts, support the hypothesis that duf-lacZ expression marks the subset of adepithelial cells that act as muscle founders for the DFMs (Kozopas, 2002).

Additional support for the hypothesis that there are cells that act as founders for the DFMs comes from the finding that apterous (ap) is expressed in the DFMs when they are first forming, around 24-36 h APF. ap is a LIM homeodomain protein expressed in embryonic muscle founder cells and is required for specific embryonic muscle identities. Using an apterous enhancer trap line, ß-galactosidase expression has been observed in many, if not all, of the developing DFMs, including the primordia of muscles 49-54, based on their morphology and attachment sites. Like duf-lacZ, ap-lacZ is expressed in small groups of cells that will form the DFM myotubes. There is a second class of myoblasts that does not express ap-lacZ, which congregates with the myoblasts and developing muscles that do express ap-lacZ. The expression of both duf-lacZ and ap-lacZ in a subset of the myoblasts that give rise to the DFMs strongly suggests that these cells function analogously to the embryonic founder cells, first promoting the fusion of naive myoblasts and then specifying their transcriptional activity. ap-lacZ is expressed in DFMs during their development and is required in a cell-autonomous manner in myoblasts for DFM development (Kozopas, 2002 and references therein).

Having determined that Wnt-2 activity is only needed during pupation for DFM development, it was asked where it is expressed at that time. In the pupal wing disc at 7 h APF, Wnt-2 mRNA is strongly expressed in the wing blade, the wing hinge primordia, and the ventral pleura. Most of these regions of expression appear to be areas where sites of third instar larval disc expression is maintained. Wnt-2 expression in the wing blade and notum appears to fade by 24 h APF, and expression in the wing hinge region becomes the most prominent feature. As the wing hinge epithelium takes on its final form, it contracts and undergoes extensive morphogenesis, including the invagination of the apodemes to which the DFMs attach. At 24 h APF, Wnt-2 is expressed in both the dorsal and ventral compartments of the wing hinge, in regions with very close proximity to one another. Wnt-2 expression in the hinge is maintained at least until the newly formed muscles have established contact with their epithelial sites of attachment at 40 h APF. Wnt-2 expression is never seen in myoblasts themselves or in the epithelial cells that serve as attachments, only in adjacent epithelial regions (Kozopas, 2002).

To determine where the DFM myoblast precursors are located relative to the expression of Wnt-2 in the wing hinge epithelium, double-labelings were performed for duf-lacZ and Wnt-2 expression. Expression of Wnt-2 is found in the wing hinge primordium adjacent to sites contacted by the duf-lacZ-expressing cells. The myoblasts at this stage (6 h APF) are not in direct contact with the region of the epithelium that expresses Wnt-2, but occupy lateral positions several cell diameters away. The fact that myoblasts reside adjacent to epithelial cells expressing Wnt-2 was confirmed by using a different marker for myoblasts, the MEF-II transcription factor that is required for muscle differentiation. These double-labelings also show that the myoblasts come in close proximity to the epithelial cells that express Wnt-2 (Kozopas, 2002).

It was asked whether Wnt-2 expression in the wing hinge adjacent to developing DFMs plays a permissive or an instructive role in their patterning. By expressing Wnt-2 in the developing wing hinge in regions that differ from the endogenous expression, defects were caused in DFMs that do not normally rely on Wnt-2 for their correct patterning. The E132:Gal4 driver, whose broad expression in the wing hinge epithelium encompasses the primordia of attachment sites for muscles 49, 50, 53, and 56, was used to misexpress UAS:Wnt-2. The resulting flies have severe DFM mispatterning defects, including the absence of muscle 49, which is never affected in the Wnt-2 mutant. Additionally, there are misattachments of muscle of a type that do not occur in the mutant, such as confusion between the attachments of muscles 50 and 53 (Kozopas, 2002).

The gene stripe (sr) encodes a transcription factor that is required in epithelial cells for their differentiation as attachment sites. Studies of IFM formation have shown that sr is expressed in early pupal development in the epidermal cells that will serve as adult IFM attachment sites. The expression of sr was examined in the adult by following ß-galactosidase reporter gene expression in the P1618 enhancer trap line. sr-lacZ is expressed in the cells that form the epidermal attachment sites for the DFMs). These attachment sites are prefigured by sr-lacZ expression in regions of the wing hinge primordia in the pupa. Some of the regions that express sr-lacZ will invaginate to form apodemes, which are points of DFM attachment. While Wnt-2 expression in the wing hinge primordia is adjacent to some of the sites of sr expression, in no region are they coincident. However, the potential for secreted Wnt proteins to diffuse away from their source renders it possible that Wnt-2 might regulate stripe expression in adjacent cells. For this reason, the expression of sr was examined in the Wnt-2 mutant. However, no changes were found in sr-lacZ expression in the primordia of the DFM attachment sites. Neither is sr-lacZ expression altered when Wnt-2 is ectopically expressed in the pupal wing hinge such that muscle patterning defects occur. These results indicate that, although Wnt-2 is required for the proper attachment of muscle to the epidermis, it does not affect sr expression, the most upstream known component of EMA cell differentiation (Kozopas, 2002).

Thus Wnt-2 is expressed in the epithelium of the pupal wing hinge, adjacent to developing DFMs and the EMA cells that serve as their attachment sites. This expression occurs during the time period that Wnt-2 is needed to mediate formation of the proper connections between these tissues. When ectopically expressed, Wnt-2 can alter the development of DFMs that do not normally depend on it and can result in muscles choosing the wrong attachment sites. The inability of Wnt-2 to regulate stripe expression in EMA cells demonstrates that Wnt-2 exerts control over muscle attachment through some mechanism other than the initiation of EMA cell differentiation (Kozopas, 2002).

The unique feature of DFM development may merely be that each adult muscle uses a group of cells to act as 'cofounders'. These groups represent the same cells referred to as 'feeder' myoblasts. Presumably, these cells would share an identity conferred by transcription factors such as ap. It is not known whether cells in these clusters fuse with one another, which would be contradictory to the behavior of duf-expressing founder cells in the embryo. It is plausible that cells in the clusters do not fuse with one another, but instead that each helps to seed syncytial growth of the muscle that will take on their shared identity. In this respect, each cluster of founder cells would represent an equivalence group. The group’s muscle identity might be conferred by the same mechanism of ectodermal signaling that specifies individual founders in the embryo. It is possible that Wnt-2 might be one of these ectodermal signals, acting similarly to wg to control the transcription of genes in adult founders that specify DFM identities. Thus, muscle attachment defects in the mutant would be the result of muscles lacking the proper identity. However, it is not known when the cells that appear to function as DFM founders are specified with regard to the muscle identities that they will assume in the adult. For the adult abdominal muscles, there is evidence to suggest that muscle identities are generated during embryogenesis. Specifically, the myoblast progenitors of the ventral adult precursors and the lateral adult precursors (VaP and LaP) are formed through asymmetric cell divisions that yield one adult muscle precursor and one embryonic muscle founder. Although there is no evidence to indicate that the diverse adult DFM identities are also generated during embryogenesis, it is a compelling theory that all adult muscle precursor cells are the siblings of embryonic muscle founders, arising through asymmetric division of muscle progenitor cells. The presence of the duf-lacZ-expressing DFM precursors as a stereotyped ventral subset of adepithelial cells in the prepupal wing disc seems to indicate that these cells have already made significant cell-fate decisions by this stage. Adepithelial cells associated with larval leg discs do have restricted cell fates, as evidenced by experiments in which ablation of myoblasts during larval stages results in missing subsets of adult leg muscles. If the myoblasts associated with the wing disc are also already programmed by early larval stages for particular DFM identities, then Wnt-2 cannot exert its effect by specifying particular muscle founder cell fates, since it is only required during pupation. For this reason, and the probable conservation of the mechanism that generates adult muscle precursors from asymmetric divisions in the embryo, Wnt-2 is an unlikely candidate to affect intrinsic muscle identity. It is a more tenable hypothesis that the Wnt-2 signaling molecule in the pupal wing hinge primordium enables muscles to attach to their correct sites, in some way facilitating these recognition events (Kozopas, 2002).

One potential function for Wnt-2 might be in directing the differentiation of EMA cells as distinct apodemes. For instance, there may be specific adhesion molecules or guidance cues expressed in attachment sites that allow resident muscles to distinguish their sites from neighboring attachments, and which Wnt-2 might regulate (Kozopas, 2002).


GENE STRUCTURE

cDNA clone length - 2.5 kb


PROTEIN STRUCTURE

Amino Acids - 352

Structural Domains

Two novel Drosophila Wnt homologs, Wnt2 and Wnt3, map (respectively) to chromosome 2 position 45E and chromosome X position 17A/B. Wnt2 and Wnt3, like the other known Wnt genes, encode amino-terminal signal peptides. This suggests that the gene products are secreted proteins. The putative translation product of Wnt2 and the carboxy-terminal half of the deduced Wnt3 product are both rich in conserved cysteine residues. Two cysteine residues, absent from Wingless and mouse Wnt-1, are conserved between Wnt2, Wnt3 and all other mouse Wnt proteins known. There is also one cysteine residue unique to mouse Wnt-1 and Wingless. In comparison with other Wnt gene products (the majority of which are approximately 40 x 10[3] relative molecular mass), the Wnt3 protein has an extended amino terminus and a long internal insert, and its predicted relative molecular mass is 113 x 10(3). The Wnt2 evolutionary relationship is marginally closest to mouse Wnt-7, as compared to other mouse Wnts (Russell, 1992).


EVOLUTIONARY HOMOLOGS

Formation of the vertebrate limb requires specification of cell position along three axes. Proximal-distal identity is regulated by the apical ectodermal ridge (AER) at the distal tip of the growing limb. Anterior-posterior identity is controlled by signals from the zone of polarizing activity (ZPA) within the posterior limb mesenchyme. Dorsal-ventral identity is regulated by ectodermally derived signals. Recent studies have begun to identify signaling molecules that may mediate these patterning activities. Members of the fibroblast growth factor (FGF) family are expressed in the AER and can mimic its proximal-distal signaling activity. Similarly, the gene Sonic hedgehog (Shh) is expressed in the ZPA, and Shh-expressing cells, like ZPA cells, can cause digit duplications when transplanted to the anterior limb margin. In contrast, no signal has yet been identified for the dorsal-ventral axis, although Wnt-7a is expressed in the dorsal ectoderm, suggesting that it may play such a role. To test this possibility, mice were generated lacking Wnt-7a activity. The limb mesoderm of these mice shows dorsal-to-ventral transformations of cell fate, indicating that Wnt-7a is a dorsalizing signal. Many mutant mice also lack posterior digits, demonstrating that Wnt-7a is also required for anterior-posterior patterning. It is proposed that normal limb development requires interactions between the signaling systems for these two axes (Parr, 1995).

Growth and patterning of the vertebrate limb are controlled by the ridge, posterior mesenchyme, and non-ridge ectoderm. Fibroblast growth factor 4 (FGF4) and Sonic hedgehog (SHH) can mediate signaling from the ridge and posterior mesenchyme, respectively. Dorsal ectoderm is required together with FGF4 to maintain Shh expression. Removal of dorsal ectoderm results in loss of posterior skeletal elements, which can be rescued by exogenous SHH. Wnt7a, which is expressed in dorsal ectoderm, provides the signal required for Shh expression and formation of posterior structures. These results provide evidence that all three axes (dorsoventral, proximodistal, and anteroposterior) are intimately linked by the respective signals WNT7a, FGF4, and SHH during limb out-growth and patterning (Yang, 1995).


Wnt oncogene analog 2:
Biological Overview | Developmental Biology | Effects of Mutation | References

date revised: 20 October 2002

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