Microarray chips (Affymetrix) were used to study the gene expression profiles of gastrulating embryos derived from wild-type, dorsal–/– and Toll10b flies. Toll10b codes for a gain-of-function Toll receptor. Many known target genes, such as twist, snail, short gastrulation, tinman and mef2, showed lower expression in the dorsal–/– sample and increased expression in the Toll10b sample, as predicted. Among the novel targets, the annotated gene CG8458 was selected for further study because it encodes a member of the Wnt family, and Wnt proteins have been implicated in controlling cell polarity and cell movement in many organisms (Ganguly, 2005).
In situ analysis reveals that wntD mRNA is expressed in a dynamic pattern in the early embryo. There is no detectable maternally deposited RNA and the earliest zygotic expression is present at the anterior and posterior poles of early stage 4 embryos. Soon after, wntD is expressed in a few patches of ventral cells. This low level of expression remains in the ventral cells throughout the blastoderm stage. Meanwhile, expression arises in two lines of cells abutting the mesoderm. These two lines of staining coincide with the mesectoderm, the precursor of ventral midline cells. The expression of wntD in the mesectoderm persists during germ band extension and gradually disappears. De novo expression appears around stage 8 in the ventral neuroectodermal cells adjacent to the midline. This expression continues in the neuroectoderm through stages 9 and 10, and is reduced to an undetectable level by stage 11. No expression was detected in other stages of embryonic development. The expression pattern of wntD is largely different from other Drosophila Wnt genes (Ganguly, 2005).
Double in situ hybridization to determine the location of the two lateral lines of wntD expression. Previous reports demonstrate that sim is expressed in the mesectoderm and is strongly repressed by Snail in ventral cells. Embryos that contained both wntD and sim in situ probes showed essentially the same lateral pattern as embryos that contained either probe, demonstrating that the two patterns overlap. Double in situ hybridization also showed that, similar to sim, the lateral expression of wntD is at the border of the snail pattern. Thus, it is concluded that the two lateral lines of wntD expression are in the mesectoderm (Ganguly, 2005).
The dorsal-ventral (D-V) axis of the Drosophila embryo is initially patterned by a ventral-to-dorsal nuclear gradient of Dorsal protein activity under the control of Spatzle/Toll signalling. Toll activates Dorsal primarily through the degradation of Cactus, thereby freeing Dorsal to enter the nucleus and activate or repress target genes. The transcriptional profile that is regulated by Dorsal defines the spatial organization of tissues in the embryo, with ventral-most cells becoming mesoderm, flanked by the mesectoderm and neuroectoderm in more lateral regions, and gut primordia at the poles (Gordon, 2005).
The gene wntD was identified as a member of the Drosophila Wnt family based on a genomic search for Wnt-related genes (synonyms CG8458 and wnt8; Llimargas, 2001). Examination of wntD RNA in situ revealed that the first detectable expression is seen at the ventral poles of the blastoderm embryo, followed by sequential ventral-to-dorsal expression in the presumptive mesoderm, mesectoderm and neuroectoderm. Embryos derived from mothers carrying a dominant, activated allele of Toll, express wntD RNA more broadly and at higher levels than wild type. This demonstrates that wntD expression is induced by Toll signalling. Examination of WntD protein distribution shows that WntD is secreted and travels multiple cell diameters away from producing cells, suggesting that WntD is capable of signalling at a distance (Gordon, 2005).
To uncover the signalling activity of WntD in the embryo, WntD was ectopically expressed in the female germline, producing blastoderm stage embryos that contain high levels of WntD protein. These embryos lacked detectable nuclear Dorsal; although total cellular levels of Dorsal protein remained unchanged. Consequently, the mesodermal Dorsal target gene Twist was not expressed, and the embryos produced only dorsal cuticle. Furthermore, the observed defects were specific to dorsal-ventral patterning, since the anterior-posterior patterning gene hunchback was unaffected by WntD (Gordon, 2005).
In order to determine the point of intersection between WntD activity and the Toll/Dorsal pathway, flies that overexpress WntD and carry strong hypomorphic alleles of cactus were constructed. Although maternal cactus mutants exhibit a ventralized phenotype, those also overexpressing WntD are dorsalized, and indistinguishable from embryos overexpressing WntD alone. These data demonstrate that WntD (a secreted growth factor) is capable of producing a signal that blocks Dorsal nuclear translocation downstream of, or in parallel to, Cactus. It has been shown previously that Dorsal undergoes Toll-dependent and -independent phosphorylation, and that Dorsal nuclear localization can be regulated independently of Cactus (Drier, 2000; Gordon, 2005)
That WntD is a member of the Wnt family of growth factors raises the question of whether it signals through the well-characterized Frizzled/Armadillo (beta-catenin) pathway. It is suggested that WntD does not, based on two lines of evidence: (1) germline clones of axin, a negative regulator of Armadillo, do not produce dorsalized embryos, and (2) overexpression of WntD in tissues sensitive to Armadillo signalling does not have any detectable effect. These observations however, do not rule out the possibility that WntD signals through a Frizzled receptor in an Armadillo-independent manner (Gordon, 2005).
In order to investigate the role of endogenous WntD, a loss-of-function mutation was constructed using 'ends-out' gene targeting. The modified wntD locus produced no detectable protein, as assayed by Western blot. Analysis of flies homozygous for either of two knockout alleles (labelled wntDKO1 or wntDKO2) revealed that wntD is not essential for viability or fertility (Gordon, 2005).
Despite their viability, wntD mutant embryos show an expansion of nuclear Dorsal into the pole regions where endogenous WntD is first detected. This indicates that the earliest role of WntD in the embryo is to restrict the field of Dorsal activation, thereby ensuring the establishment of the proper boundary between the developing ventral and terminal domains; Dorsal, along with A-P positional information, induces transcription of wntD at the ventral poles of the embryo, and WntD in turn feeds back to repress Dorsal nuclear translocation, and prevent improper spread of the ventral domain. This mechanism stands in contrast to another characterized mode of Dorsal pathway repression at the embryonic termini -- that of signalling from the Torso (Tor) receptor tyrosine kinase. In the case of Torso, signalling at the poles of the embryo selectively interferes with the ability of Dorsal to repress the expression of specific target genes, although exerting only a minor effect on those genes activated by Dorsal. These data suggest that Torso signalling affects the activity of nuclear Dorsal, whereas WntD signalling affects Dorsal's nuclear translocation (Gordon, 2005).
In addition to its role in D-V patterning, it has been well established that Toll/NF-kappaB signalling has a more evolutionarily conserved role in regulating the innate immune system. During the immune response Toll induces the nuclear translocation of two NF-kappaB family members: Dorsal and Dorsal-related immunity factor (Dif). Genetic analysis has suggested that Dif, although dispensable for development, is the major transcription factor involved in the Toll-mediated immune response. In addition to Dorsal and Dif, the fly immune response also uses a third NF-kappaB related protein, Relish, which is activated on signalling by PGRP-LC (Choe, 2002) and Imd (Hedengren, 1999). Together, these pathways regulate the expression of hundreds of genes after microbial infection (Gordon, 2005).
In light of the interaction between WntD and Dorsal in the embryo, it was asked if WntD could have a role later in the fly's life as a repressor of Toll/Dorsal-mediated immunity. Polymerase chain reaction with reverse transcription (RT-PCR) was used to confirm expression of endogenous wntD RNA in adults. wntD mutant adults appear normal, with the exception that at low frequency (1%-2%) sites of ectopic melanization have been observed, most notably on the wing hinge. This is consistent with a role for WntD in maintaining low basal levels of Toll/Dorsal signalling; other mutations that hyper-activate Toll show increased levels of phenoloxidase-driven melanization. Furthermore, Dorsal has been shown to be an essential component of the melanization response in larvae (Gordon, 2005).
To investigate the role of WntD after septic injury, wntD and control flies were injected with a dilute culture of the gram-positive bacterium Micrococcus luteus, and the induction of antimicrobial peptide (AMP) transcripts were monitored over time using quantitative RT-PCR. It was observed that some, but not all, AMPs showed aberrant expression in wntD mutants. The AMP diptericin is most severely affected, with wntD flies displaying dramatically elevated basal levels of expression (approximately 15-fold), and significantly higher mRNA levels following infection. In contrast, Drosomycin mRNA levels were not significantly different from controls in either uninfected or infected wntD mutants. A third AMP, defensin, showed an intermediate pattern of expression, with elevated mRNA levels in wntD mutants at some time points (Gordon, 2005).
These results pose an apparent paradox, since previous experiments have characterized diptericin as a target of IMD/Relish, and drosomycin as a target of Toll signalling. Drosomycin expression is reported to be primarily regulated by Dif in adult flies, and appears to be unaffected by increased Dorsal activity. Thus, the results for Drosomycin are consistent with past work. The diptericin result initially appears puzzling, but existing data demonstrate that the signal transduction pathways regulating immunity are not as specific as initially described. For example, Relish is required for diptericin induction in response to infections in vivo, but constitutive activation of Toll signalling results in elevated levels of diptericin in adult flies. Furthermore, Dorsal is sufficient to activate the diptericin promoter in vitro. The simplest explanation for these observations is that diptericin transcription can be induced by Toll/Dorsal signalling. Taken together, these data support a model in which WntD signalling specifically represses Toll/Dorsal, and not Toll/Dif signalling (Gordon, 2005).
Given a role for WntD in the regulation of antimicrobial gene transcription, attempts were made to determine whether wntD mutants were immunocompromised. To test this, wntD and control adults were infected with the gram-positive, lethal pathogen Listeria monocytogenes. In response to infection, wntD mutants exhibit significantly higher levels of mortality when compared with parental lines. Importantly, this phenotype is suppressed by the introduction of dorsal mutations, with close to full suppression in the absence of both copies of dorsal and partial suppression in flies heterozygous for a dorsal mutation. These genetic interactions are consistent with the assertion that WntD specifically regulates Dorsal, and not other mediators of immunity. Recent reports have demonstrated that a fly's response to bacterial challenge includes factors that are damaging to the host, and that increased Toll signalling can render flies more susceptible to viral infection. It is therefore proposed that it is the deleterious hyper-activation of specific Dorsal target genes that is responsible for the increased mortality seen in wntD mutants. Furthermore, the susceptibility of wntD mutants to a lethal infection suggests a reason for the positive selection of wntD during evolution; immune responses have a cost, and their appropriate downregulation would be expected to provide flies with a selective advantage. Although wntD flies appear healthy in a lab environment, it is easy to imagine that under the more stressful, and septic, conditions in the wild, flies lacking wntD would suffer the perils of a hyperactive immune system (Gordon, 2005).
This study has presented evidence that WntD, a Wnt family member, produces a signal that blocks the nuclear translocation of Dorsal. Furthermore, WntD is a target of Toll/Dorsal signalling, and creates a negative feedback loop to repress Dorsal activation. wntD is not required for viability under lab conditions, but wntD mutants show defects in embryonic Dorsal regulation, and in the adult innate immune system. Since the WntD signal in the embryo is not mediated by Armadillo, it is supposed that the immune function of WntD is also Armadillo-independent, although immune defects have been observed in flies expressing a dominant-negative form of the Aramdillo partner DTCF. Further characterization of signalling events bridging WntD and Dorsal could yield valuable insight into the regulation of the therapeutically important NF-kappaB family of proteins (Gordon, 2005).
An essential biological function of the Dorsal/Twist/Snail network is to promote invagination of the ventral cells to form the mesoderm. Although the repressor function of Snail is required for ventral invagination, none of the known target genes normally repressed by Snail has been directly implicated in disrupting ventral invagination. Because wntD is repressed by Snail, wntD expression was increased in wild-type embryos in an attempt to phenocopy the defects in snail mutant embryos. The maternal nanos-Gal4 line was used to direct the ubiquitous expression of UAS-wntD in early embryos. It was found that approximately 50% of these embryos at the gastrulation stage had observable defects in ventral invagination. Approximately one quarter of these defective embryos had completely lost the ventral furrow, and the others showed varying degrees of invagination with the anterior regions always being worse than the posterior regions. The ventral invagination defect is not a result of general problems in cell shape changes or cell movements because cephalic furrow formation and germ-band extension occurs normally in these embryos. Tissue sectioning confirmed the phenotype that the mesoderm is largely missing in gastrulating embryos (Ganguly, 2005).
The nanos-Gal4 female flies deposit maternally the Gal4 gene products, which direct the UAS-dependent WntD expression ubiquitously in pre-blastoderm stage embryos. The rhomboid-Gal4 driver was tested; this rhomboid promoter contains mutations in its Snail-binding sites and directs zygotic Gal4 expression in the ventral half of the blastoderm. In these experiments, approximately 5% of embryos at gastrulation stage show slightly defective invagination. The rhomboid promoter, as well as other ventral zygotic promoters, is activated by Dorsal. Thus, the expression of WntD by zygotic promoters may be too late to induce a substantial phenotype. This speculation is consistent with the proposed mechanism of feedback inhibition of Dorsal by WntD (Ganguly, 2005).
The Wnt family of secreted proteins regulates cell fate, cell polarity, cytoskeleton and cell movement. To elucidate the mechanism that underlies the invagination defect induced by WntD, various markers of cell fate and cell shape were examined. It was surprising to find that twist and snail expression becomes highly abnormal in the nanos-Gal4-driven WntD-expressing embryos. The twist pattern was narrower than 12-cell widths along the circumference, compared with 20-cell widths in wild-type embryos. The snail expression pattern was even more severely affected. A total of 93% (n=147) of WntD-expressing embryos at the blastoderm and gastrulation stages showed abnormality in the snail expression pattern. The abnormality was variable and ranged from a few cells narrower to an almost complete disappearance of the pattern. The anterior expression was always more severely affected, and the posterior expression was affected to various extents in different embryos. The phenotype was quantitated by counting the width of the snail expression domains at 50% egg-length. In WntD-overexpression embryos that were assigned to have a phenotype, the snail pattern varied from zero to 11 cells, with an average width of seven cells. For wild-type embryos, the width of the snail domain is 13 to 17, with an average of 15 cells. Thus, all the embryos that were assigned to have a phenotype showed quantitative defects (Ganguly, 2005). sim and rhomboid are normally repressed by Snail in the presumptive mesoderm. In WntD-overexpression embryos the sim pattern disappears in the anterior region and the lateral rows of staining come closer in the posterior region. Snail represses sim expression in the ventral cells but the expression and positioning of sim in the presumptive mesectoderm also requires Snail. Therefore, the abnormal sim pattern follows exactly the reduced snail expression. rhomboid shows similar narrowing of the pattern, consistent with the model that Snail is a simple repressor of rhomboid. In conclusion, increased WntD expression causes highly reduced twist and snail expression, leading to abnormal expression of other genes in ventral cells. Even though increased WntD expression may also cause other defects, the reduced twist and snail expression is probably sufficient to account for the loss of invagination (Ganguly, 2005).
The direct activator of twist and snail expression in the blastoderm is Dorsal. Therefore, the distribution of the Dorsal protein was examined. In wild-type blastoderm and gastrulating embryos, Dorsal shows the characteristic ventral nuclear pattern. By contrast, WntD overexpression causes low-level staining around the periphery of the whole embryo, and high-resolution imaging showed that the ventral cells have Dorsal proteins predominantly in the cytoplasm. This phenotype is similar to that of embryos derived from a gastrulation-defective mutant, which causes no activation of the Toll pathway. Embryos derived from the opposite Toll10b gain-of-function mutant show nuclear staining all around the embryo. The phenotype induced by WntD overexpression is different from that in the Dorsal protein null mutant, which essentially showed no staining. These results together suggest that the overexpressed WntD inhibits Dorsal nuclear localization (Ganguly, 2005).
Specific mutants of wntD are not yet available. Therefore, a few deficiency strains were examined by staining for wntD mRNA expression in the embryo; it was confirmed that Df(3R)l26c, which has the 87E1-87F11 region deleted, has uncovered wntD. This deficiency was used to assess whether endogenous WntD regulates Dorsal. In wild-type blastoderm, the Dorsal nuclear gradient extends into the neuroectoderm and the posterior end. Before the onset of gastrulation, the posterior Dorsal staining is normally retracted. However, in embryos derived from the Df(3R)l26c strain, Dorsal nuclear staining expands in the posterior region. Because the earliest wntD expression is at the anterior and posterior regions, the loss of wntD in the deficiency could be the underlying reason for the posterior expansion of Dorsal in these embryos (Ganguly, 2005).
The posterior expression of snail in wild-type embryos is retracted and shows a sharp pattern before the onset of gastrulation. snail expression in Df(3R)l26c mutant embryos, however, expands into the posterior region. Double staining shows that, in wild-type embryos, the posterior gene huckebein is complementary to the snail pattern. No change was detected in the huckebein pattern in the Df(3R)l26c mutant embryos. Using huckebein expression as a position marker, it was found that the snail pattern expands into the posterior region so that it overlaps with that of huckebein in the deficiency mutant embryo. Quantitation by using the snail pattern revealed that 24% (n=55) of all gastrulating embryos from Df(3R)l26c heterozygous parents showed the posterior expansion. Based on Mendelian ratios, this result represents an almost full penetrance. Thus, there is a posterior expansion of snail expression that correlates with the posterior expansion of nuclear Dorsal. Subtle broadening of the snail pattern was also observed in the anterior region, suggesting that there is an increase of nuclear Dorsal in the anterior region, but the increase was not detectable by immunofluorescence staining (Ganguly, 2005).
Because Df(3R)l26c removes a number of genes in addition to wntD, a genetic rescue experiment was performed to confirm the involvement of wntD. A transgenic line that contained a wntD genomic fragment was generated that showed all the normal expression patterns of wntD in the early embryo. When this genomic construct was crossed into the Df(3R)l26c mutant, the posterior and anterior expansion phenotype of snail was completely rescued. Posterior Dorsal expansion was not observed in any of the embryos derived from the wntD-rescued Df(3R)l26c strain. The rescue experiment demonstrates that the deletion of wntD in the deficiency strain is responsible for the observed Dorsal and snail expression phenotypes. RNA interference of wntD was performed by injecting double-stranded RNA into wild-type pre-blastoderm stage embryos. Approximately 10% of these injected embryos at late blastoderm stage had a mild posterior expansion of snail, and none of the embryos injected with buffer alone showed such a phenotype. This result further supports the idea that loss of WntD causes posterior expansion of snail expression (Ganguly, 2005).
Whether the de-repressed WntD expression in the ventral cells of snail mutant embryos can inhibit Dorsal function was examined. A previous report demonstrated that in mutant embryos that produced non-functional Snail proteins, the expression of snail mRNA disappears prematurely. This premature loss of snail mRNA expression could be due to the inhibition of Dorsal function by the de-repressed WntD. It was surmised that the removal of wntD in a snail mutant should lead to enhanced Dorsal function. Thus, a snail;Df(3R)l26c double-mutant strain was established. The double homozygous embryos were identified by the lack of wntD mRNA staining and the lack of a ventral furrow. The snail mRNA pattern in snail mutant embryos exhibited a fuzzy border around the onset of gastrulation. By contrast, double-mutant embryos showed a snail pattern with sharp borders, similar to that observed in wild-type or Df(3R)l26c embryos. The developmental stages of these embryos were very similar based on the position of the pole cells, the degree of cellularization, and the cephalic furrow formation, supporting the argument that the genetic defect is the cause for the change of snail pattern. By mid-germ band extension, the snail mRNA staining became very weak in snail mutant embryos, but in double-mutant embryos the snail mRNA level was better sustained. The establishment and maintenance of the sharp snail pattern requires Dorsal. The Df(3R)l26c deficiency strain has many genes deleted and the effect cannot be attributed directly to the loss of wntD, but the result is consistent with the speculation that deleting wntD in the snail mutant embryo allows Dorsal to function more efficiently in activating target genes (Ganguly, 2005).
Reference names in red indicate recommended papers.
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date revised: 20 December 2009
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