The expression pattern of shf was analyzed by in situ hybridization in wild-type and P-element line EY03173 imaginal discs. Specific probes complementary to sequences encoding the EGF-like domains of the Shf/DmWIF protein were used, because the P element insertion in line EY03173 was located before these domains. No signal was seen in EY03173 imaginal discs. However, wild-type third instar wing imaginal discs showed a pattern comprised of higher levels in the most anterior and posterior parts of the disc and low or null levels at the A/P compartment border. The leg discs and the antenna part of the eye-antennal imaginal disc also show downregulation at the A/P compartment border. The eye primordium displays the downmodulation of Shf/DmWIF expression in the morphogenetic furrow. It was surprising to find low levels of Shf/DmWIF transcripts in regions of the disc where the function of the gene was required. At the blastoderm stage, shf is ubiquitously expressed, indicating a maternal component. As embryogenesis continues, shf is expressed in the epidermis and central nervous system, and this expression is segmentally modulated. shf also showed very high expression levels at the foregut and hindgut throughout embryogenesis. Germline clones of shfEY03173 allele do not show phenotype alterations during embryogenesis, suggesting that neither maternal nor zygotic shf is essential for embryonic development. The shf requirement for Hh diffusion only during disc development is in agreement with Hh signaling over several cellular diameters in the wing disc, in contrast to the short-range Hh signaling during embryogenesis (Gorfinkiel, 2005).

In situ hybridization to imaginal discs from third instar larvae shows patterned expression of shf mRNA in the wing disc, with higher levels of shf mRNA accumulating in parts of the notum and in the anterior and posterior edges of the wing pouch. Neither of the wing pouch domains appears to conform to or precisely delimit the anterior or posterior compartments (Glise, 2005).

Effects of Mutation or Deletion

Two alleles of shf have been described: shf2 and shf919. shf2 and shf919 flies are semiviable, showing a small body and reduced fertility. In these alleles, wing vein L3, the anterior cross-vein, the distance between veins 3 and 4 are affected and the posterior scutellar bristles are also abolished. This phenotype is characteristic of alleles of genes required for activation of the Hh pathway, such as smoothened (smo), fused (fu) or cubitus interruptus (Ci). This behavior is also observed in other mutants affecting Hh release, Hh transport, or Hh modifications such as Dispatched, a transmembrane protein required for Hh release, the EXT proteins, and sightless. The expression of Hh targets at the A/P compartment border of shf2 wing discs such as Ptc, Ci, En, Dpp, and Col was determined and it was found that their expression domains are reduced, as when Hh signaling is diminished. Hence, shf seems to be another component of the pathway (Gorfinkiel, 2005).

To analyze the epistatic relationship between shf and other components of the Hh pathway, the Hh response was first examined in the A compartment of wing discs double mutant for shf and the Hh receptor Patched (Ptc). Ptc has two described roles: to block Hh signaling and to sequester Hh. These two Ptc roles were shown in ptc- clones abutting the A/P compartment border. Thus, Hh targets are activated inside the clone but also in the wild-type cells located anterior to the clone, because in the absence of Ptc, there is no restriction in the range of Hh transport, and Hh diffuses through the clone. In ptc- clones in a shf2 background, Hh targets are also fully activated inside the clones, indicating that ptc acts downstream from shf in Hh signaling. However, Hh targets are not activated in the wild-type cells anterior to the clone, as shown by the lack of activation of Ptc, Ci, and Col in these cells, suggesting that shf is required for the production, secretion or diffusion of Hh (Gorfinkiel, 2005).

The involvement of shf in Hh production or diffusion or secretion was further suggested by inducing clones of an allele of ptc that does not show much restriction to Hh diffusion, in a shf2 background. The ptc14 allele fails to sequester Hh but can undergo normal signaling in response to Hh (Torroja, 2004). ptc14 mutant clones do not activate Hh targets in the absence of Hh, but they extend the Hh gradient at the A/P compartment border as shown by the expansion of the expression of the Hh target genes such as ptc itself. Nevertheless, ptc14 clones abutting the A/P compartment boundary in a shf2 background did not extend the Hh gradient as shown by normal activation of the Hh targets at the A/P border inside ptc14 mutant clones. These findings again indicate that shf2 is acting upstream from Ptc in Hh signal transduction and is required for the production of the Hh source that reaches the A compartment, either for Hh expression or secretion or stability in the P compartment cells, or for Hh spreading (Gorfinkiel, 2005).

To establish whether the expression of hh was affected in shf mutants, first the levels of Hh transcription were analyzed in shf mutant compared with a wild-type wing disc. By quantitative RT-PCR, it was determined that the levels of Hh transcription in shf EY03173 were the same as wild-type background. Also, in a double staining for hh-LacZ and Hh protein, it was observed that levels of Hh transcription are normal in shf mutants disc cells; however, the levels of Hh are 40% reduced in shf EY03173. In particular, the distribution of Hh protein in the plasma membrane is lower in shf mutant discs than in wild-type discs, and this Hh reduction occurs in both apical and basal lateral regions in shf mutant discs (Gorfinkiel, 2005).

Lipid-modifications of Hh are required for its plasma membrane localization in the embryo. Therefore the behavior of wild-type Hh compared to the nonmodified lipid forms of Hh was evaluated in shf imaginal discs. For this purpose, use was made of a Hh-GFP fusion protein that behaves as the wild-type protein in terms of signaling and diffusion (Torroja, 2004) and of HhN and HhC85S (without cholesterol and without palmitic acid, respectively) fused to GFP (HhN-GFP and HhC85S-GFP), which also behaves as predicted. When Hh-GFP was expressed with the ap-GAL4 line, it was observed that although the signaling ability of Hh-GFP is normal in shf2 mutants, Hh-GFP is unable to diffuse in neither the A or P compartments in shf2 mutant imaginal discs as compared with wild-type discs. In contrast, neither HhN-GFP nor HhC85S-GFP diffusion is affected in shf2 mutants compared to wild-type discs and also signaling of these unmodified forms of Hh is as in wild-type background. It is concluded that shf is required for lipid modified Hh diffusion in both the A and P compartments (Gorfinkiel, 2005).

shf alleles were mapped by recombination to 1-17.9 and cytologically to 6D1-E5 (6A3-F11). To obtain a stronger shf allele, imprecise excisions of a nearby P element (EP1613) were generated, which gave a shf phenotype when heterozygous with shf2. Several chromosomal deletions and the smallest one (Df(1)2.5) uncovered three transcription units: the COQ7 gene, which encodes a protein required for ubiquinone metabolism; the C3G gene, which encodes a Ras-guanyl nucleotide exchange factor (Ishimaru, 1999); and CG3135, which codes for the Drosophila homolog of the vertebrate Wnt inhibitory factor DmWIF (WIF-1; Hsieh, 1999). Homozygous Df(1)2.5 animals die as third instar larvae. The imaginal discs of these larvae do not grow properly and have reduced Hh target expression domains at the A/P compartment border. It has been shown that the expression of a constitutive active form of C3G causes overproliferation in wing discs. Thus, attempts were made establish whether the phenotype of the lack of proliferation was due to the lack of either C3G or DmWIF. When DmWIF was overexpressed in imaginal discs of mutant larvae using a generalized expression GAL4 line, the rescue of Ptc and Ci expression at the A/P compartment border was observed, but the size of the discs was not much recovered. Further, diffusion of Hh to the A compartment was recovered when DmWIF was overexpressed in Df 2.5 hemizygous larvae. In contrast, when C3G was overexpressed, the size of the disc was much rescued but Ptc expression at the A/P compartment border was as in shf mutants. The overexpression of both DmWIF and C3G gave rise to normal-sized imaginal discs, with wild-type expression of Hh targets at the A/P border. Accordingly, it can be concluded that C3G is responsible for most of the proliferation reduction in Df(1)2.5 imaginal discs and that DmWIF is responsible for the reduced Hh target expression observed at the A/P border (Gorfinkiel, 2005).

Normal activation of the Hh targets was not affected in large shf mutant clones induced in either the A or P compartments and touching the A/P border. This indicates that the wild-type cells close to the mutant clone nonautonomously rescue the phenotype of the shf clone. To test if Shf/DmWIF can rescue the shf2 phenotype nonautonomously, Shf/DmWIF was expressed in restricted domains of shf2 or EY03173 mutant discs. When Shf/DmWIF was induced using hh-GAL4 or ap-GAL4 lines, which are expressed in posterior and dorsal compartments, respectively, the shf phenotype is normalized. This nonautonomous rescue indicates that shf encodes a secreted protein, as proposed for vertebrates (Gorfinkiel, 2005).

An extracellular modulator of Hedgehog signaling in Drosophila, Shifted, has been identified and characterized. Shifted is required for high levels of long-range signaling in the developing wing imaginal disc. Surprisingly, shifted encodes the only Drosophila ortholog of the secreted vertebrate protein Wnt Inhibitory Factor-1 (WIF-1), whose known role is to bind to extracellular Wnts and inhibit their activity. However, Shifted does not regulate Hedgehog signaling by affecting Wingless or Wnt signaling. It has been show instead that Shifted is a secreted protein that acts over a long distance and is required for the normal accumulation of Hh protein and its movement in the wing. These data further indicate that Shf interacts with Hh and the heparan sulfate proteoglycans. Therefore, it is proposed that Shf stabilizes the interaction between Hh and the proteoglycans, an unexpected role for a member of the WIF-1 family (Glise, 2005).

The Hedgehog (Hh) family of intercellular signaling molecules has essential functions during metazoan development, in both vertebrate and invertebrate organisms. In many cases, Hh acts as a morphogen, inducing distinct cell fates at different concentrations and thus conveying positional information. The precise regulation of Hh activity has important consequences for developmental and tumorigenic events (Glise, 2005).

Hh can be regulated when in transit between the Hh-secreting and Hh-receiving cells. Proteins that bind extracellular Hh can inhibit signaling. In Drosophila, the high levels of the Hh receptor Patched (Ptc) expressed in Hh-receiving cells reduce the range of Hh signaling. In vertebrates, the cell surface Hedgehog Inhibitory Protein (HIP) and the secreted Growth Arrest-Specific Gene 1 protein (GAS1) inhibit signaling (Chuang, 1999; Lee, 2001), apparently by binding Hh proteins and sequestering them from Ptc (Glise, 2005).

Drosophila lacks obvious orthologs of HIP and GAS1. However, extracellular factors have been found in Drosophila that have a positive influence on Hh signaling. The heparan sulfate proteoglycans (HSPGs) of the extracellular matrix are required for the accumulation of Hh around hh-expressing cells; moreover, removing either HS synthesis or the two Drosophila glypicans, Dally and Dally-like (Dlp), reduces the movement of Hh through Hh-receiving tissues. Thus, it has been suggested that cell bound HSPGs are involved in the movement of Hh along cell surfaces and from cell to cell, either by aiding in the diffusion of Hh or by a bucket brigade mechanism in which Hh is passed between adjacent HSPGs (Glise, 2005).

shf has been known for more than 85 years for its effects on wing development. The Drosophila wing is made from the wing imaginal disc, an epithelial sac that is subdivided from early stages into anterior and posterior compartments. Hh protein is made by posterior cells but can only signal in anterior cells, since posterior cells lack the Hh receptor Ptc and downstream effector Cubitus interruptus (Ci). Once bound to Hh, Ptc can no longer inhibit the activity of the transmembrane domain protein Smoothened (Smo), leading to the stabilization of full-length Ci and its translocation to the nucleus, where it functions as a transcriptional activator (Glise, 2005).

Hh signaling in the wing disc results in target gene activation in up to 12 rows of cells along the anterior-posterior (A/P) compartment boundary. This signaling has two main roles in patterning the developing wing. The most well-known role is indirect, via activation of decapentaplegic (dpp) expression; dpp encodes a BMP-4-like signaling molecule that moves and acts over a long range, in both the anterior and posterior directions, to control much of the growth and A/P patterning of the disc. However, Hh signaling also has a direct role, patterning the central region of the wing. Hh induces the expression of the transcription factor Collier-Knot (Col-Kn) in the presumptive intervein tissue between the third and fourth longitudinal veins (L3 and L4, respectively); Col-Kn is required for the differentiation of the central region of the wing between L3 and L4. Reducing Hh signaling can narrow the domain of Col-Kn expression and thus the size of the intervein between L3 and L4, while leaving enough dpp expression that patterning in the remainder of the wing is largely intact. Thus, the size of the L3-L4 intervein is a sensitive assay for changes in Hh signaling (Glise, 2005).

shf mutations reduce the distance between L3 and L4 in the wing (Craymer, 1980; Diaz-Benjumea, 1990; Lindsley, 1992), and shf has been shown to be required for high levels of long-range Hh signaling in the developing wing. shf encodes the only Drosophila ortholog of the secreted vertebrate protein, Wnt Inhibitory Factor-1 (WIF-1). This was unexpected, as the only known role of vertebrate WIF-1 is to bind to extracellular Wnts and inhibit their signaling (Hsieh, 1999; Hunter, 2004). However, the effects of shf on Hh signaling cannot be accounted for by gains in Wnt signaling. Rather, like the HSPGs, Shf is required for the normal accumulation of Hh protein and its movement in the wing. Moreover, data is presented suggesting that Shf physically interacts in the wing disc with Hh and the HSPGs. Therefore, it is proposed that Shf acts as a cofactor, mediating the interaction between Hh and the HSPGs (Glise, 2005).

Two of the original shf alleles are still available: shf2 (Lindsley, 1992) and shf919 (Diaz-Benjumea, 1990). shf2 flies are homozygous viable, and their wings display the typical shf wing phenotype: the distance between L3 and L4 is reduced, the number of L3 campaniform sensilla is also often reduced, and the socketed (sensory) bristles of the wing margin often extend down to L4. In addition to the wing phenotype, one or both scutellar bristles are also often missing, and a few ommatidia are abnormally arranged in the compound eye. shf919 is semilethal; while embryonic lethality was previously reported (Diaz-Benjumea, 1990), but much or all of the lethality occurs at pupal stages. Rare adult male escapers emerge that look like shf2 flies with, in addition, roughened and reduced compound eyes, reminiscent of descriptions of the lost shfoval allele (Bateman, 1950). The accumulation of shf mRNA in shf2 and shf919 wing discs is similar to wild-type (wt). Sequencing of the entire coding region showed that shf2 and shf919 contain missense mutations in the third EGF repeat, each replacing a conserved cysteine with a serine (Cys374 and Cys363 in shf2 and shf919, respectively). shf919 also contains a 10 bp deletion in the second intron (Glise, 2005).

Imprecise excision of nearby P elements was used to generate additional shf alleles. The KG04261 P element was used to create deletions lacking the transcription start identified by 5' RACE. However, while the largest of these (shfx13) had strongly reduced expression in discs, residual expression was detected by RT-PCR, indicating the existence of other start sites. Additional deletions were generated using the GE1012 P element insertion which lies just 5' to the second exon. The largest of these deletions, shfx33, removed 630 bp, including the exon 2 acceptor splice site, the ATG, and the sequence coding for the first 32 amino acids of the Shf protein, including the signal peptide. The extent of this deletion suggests that shfx33 is a null allele. The original stock was semilethal at larval and pupal stages; male escapers had slightly stronger wing phenotypes than other shf alleles, with a more pronounced narrowing of the L3-L4 region, together with, in some cases, partial deletions. These escapers also had reduced eyes and a reduced scutellum, most often lacking bristles. Outcrossing yielded a homozygous viable shfx33 stock with slightly weaker adult phenotypes; this suggests that neither maternal nor zygotic Shf is essential for viability (Glise, 2005).

The wing blade and scutellar shf phenotypes are reminiscent of those observed when Hh signaling is reduced, such as in fused mutants or hhts flies raised at restrictive temperatures. Hh mutations can also cause reduced, roughened-appearing eyes. Moreover, genetic interactions were observed between shf alleles and mutations in the Hh signaling pathway, such as fuA. These phenotypes are not simply additive, but truly synergistic; defects such as loss of L3 and L4 have been observed in regions of the wing not affected by either mutation alone (Glise, 2005).

To directly assess Hh signaling, the expression of a number of Hh targets along in the cells on the anterior side of the A/P compartment boundary was examined. In a disc from wt late third instar larvae, dpp-lacZ (BS3.0), col-kn, ptc, and engrailed (en) are expressed in stripes about 12, 7, 5, and 3 cells anterior to the A/P boundary, respectively. In shf mutant wing discs, the width of each of these stripes is drastically reduced, although the register of expression is perfectly maintained, and none is completely absent (Glise, 2005).

Hh signaling activity is largely transduced by the stabilization and activation of the full-length form of the Ci transcription factor, and the extent of Hh signaling can be monitored using a monoclonal antibody to full-length Ci. In shf2, shf919, and shfx33 discs, the width of the region with heightened anti-Ci staining is reduced when compared with wt discs, spanning two to four cells in shfx33. Furthermore, anterior expression of 4bs-lacZ, a highly sensitive Hh signaling reporter that contains four Ci binding sites, is undetectable in shfx33/Y mutants except at the distal-most tip of the wing pouch. From these observations, it is concluded that shf mutations decrease the range and level of Hh signaling and that shf acts upstream of Ci stabilization (Glise, 2005).

The only known function of human WIF-1 is to inhibit signaling via Wnts, likely by sequestering Wnts from their receptors (Hsieh, 1999; Hunter, 2004). The WIF domain from human WIF-1 (hWIF-1) can bind Xenopus Wnt8, mammalian Wnt4, and Drosophila Wingless (Wg), and misexpression of hWIF-1 inhibits the ability of these Wnts to induce a secondary axis in Xenopus embryos and to signal in vitro. WIF domains are also found in the Ryk family of atypical receptor tyrosine kinases (reviewed in Patthy, 2000). One of the Drosophila Ryks, Derailed (Drl), binds Drosophila Wnt5, and mammalian Ryk binds Wnt-1 and Wnt-3a, presumably via their WIF domains. These results suggest that all proteins possessing a WIF domain affect Wnt signaling pathways (Glise, 2005).

However, no evidence was found of any wg gain-of-function phenotypes in shf mutant flies. Conversely, the ubiquitous overexpression of shf, using either a UAS-shf transgene or an EP insertion upstream of the shf locus [EP(1)61279], does not result in any detectable loss of Wg signaling. shf-overexpressing flies are fully viable and morphologically wt, with the exception of rare cases (5%) in which the EP(1)61279; ptc-gal4 combination resulted in a single truncated hindleg. These flies lacked all of the phenotypes typical of slight reductions in Wg signaling, such as the loss of wing margin bristles. This is despite the fact that these drivers induce levels of shf expression that are much higher than those that occur in wt wing discs. Moreover, overexpressing shf in flies does not mimic any of the wnt2 and wnt4 loss-of-function phenotypes. Finally, none of the embryonic central nervous system phenotypes observed in wnt5 mutants are detected after shf misexpression or in shfx13 or shfEY03173 mutants (Glise, 2005).

It was then asked whether ectopic Wg/Wnt signaling can reproduce the shf phenotype. The effects of Wnt misexpression were tested directly by driving expression of UAS-wnt2, UAS-wnt4, UAS-wnt5, UAS-wnt6, UAS-wnt8, or UAS-wnt10 in the wing disc using the en-Gal4, Dll-Gal4, ptc-Gal4, or 32B-Gal4 drivers. In no case was a shf-like phenotype observed in the wing. Furthermore, when these experiments were performed in a shf2 mutant background, the shf phenotype was not enhanced. Nor does overexpression of the Wnt signaling effector Dishevelled in dorsal cells using apterous (ap)-Gal4, at levels sufficient to drive the formation of ectopic wing margin bristle precursors, reduce the expression of Hh targets in the disc. Thus, there is no evidence for Wnt's involvement in the shf Hh signaling phenotype in the wing (Glise, 2005).


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shifted: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 5 December 2013

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