The vertebrate gene FER encodes two protein-tyrosine kinases with molecular weights of 51,000 and 94,000 and distinctive aminotermini. The larger kinase is expressed ubiquitously among vertebrate tissues, whereas expression of the smaller kinase appears to be limited to spermatogenic cells in the testes. Drosophila contains an apparent ortholog of FER (DFer) that also produces two mRNAs by separate initiation of transcription, and two proteins with molecular weights of 45,000 and 92,000. Both proteins are in part loosely associated with cytoplasmic membranes. Both can transform avian and rodent cells with roughly equal potency, when expressed from retroviral vectors. Fusing the myristoylation signal from the SRC protein-tyrosine kinase to the aminoterminus of the DFer protein increases the strength of attachment to membranes but augments transformation only marginally. The results provide the first demonstration of neoplastic transformation by a protein-tyrosine kinase of Drosophila and by FER from any species. The products of Drosophila and vertebrate FER may be part of similar signaling pathways in the two species (Paulson, 1997).
In wild-type embryos, dorsal closure is initiated by activation of the JNK pathway in leading edge cells, resulting in the transcription of two JNK pathway targets, decapentaplegic, a TGF-ß homologue, and puckered, a dual specificity phosphatase. Dpp signals to the neighbouring epidermal cells, causing them to elongate dorsoventrally. Puc inhibits Jun kinase, initiating a negative-feedback loop. Given that both Src and DFer function in dorsal closure, and that Src is an upstream regulator of the JNK pathway, whether DFer also regulates the JNK pathway was tested (Murray, 2006),
Initially assayed was whether the activity of the JNK pathway in leading edge cells is altered in dfer loss-of-function mutants. In dferΔ1 and dferΔex1 mutants, dpp expression levels appear normal. In Src42A mutants, dpp expression is slightly reduced, becoming patchy from stage 13 onwards. In Src42A;dferΔ1 double mutants, dpp expression in the leading edge is reduced further and is almost abolished by stage 13. This suggests that DFer facilitates Src42A-mediated JNK signalling. However, neither DFerRB nor wex1-DFerRB is able to induce ectopic expression of dpp, suggesting that DFer is not itself sufficient to activate the pathway. Furthermore, JNK activation is normal in leading edge cells of dfergof mutants (Murray, 2006),
dfer transcription is upregulated in LE cells, as are dpp and puc. Although dfer transcription occurs at a later stage than that of dpp and puc, whether dfer might nonetheless be a transcriptional target of the JNK pathway was tested. In loss-of-function mutants for the Jun kinase kinase hemipterous, dpp is lost in leading edge cells. dfer, however, is still expressed. When a constitutively active form of Hep, UAS-hepCA, is expressed in the engrailed pattern, dpp is upregulated in the posterior half of each segment, but dfer is not. Therefore, dfer is not a JNK target (Murray, 2006),
Surprisingly, although dfer is not regulated by the JNK pathway, it was found that the dfergof phenotype is rescued by expression of the JNK inhibitor Puckered (Puc). UASpuc,dfergof embryos close at normal rates, resulting in a regular arrangement of epidermal cells. Axon misrouting at the ventral midline is also rescued. Since DFer is unlikely to act through the JNK pathway, Puc may suppress the dfergof phenotype by dephosphorylating either DFergof itself or its downstream targets (Murray, 2006),
DFer localises to adherins junctions (AJs) where it may regulate the phosphorylation state, and hence stability, of AJ proteins. To test whether DFer regulates the phosphorylation of ß-catenin, the extent of ß-catenin tyrosine phosphorylation was determined in dfer mutants. ß-catenin was immunoprecipitated from yw,dferΔ1 and dfergof embryos, and probed with anti-Armadillo (ß-catenin) and anti-phospho-tyrosine. In dferΔ1 embryos, ß-catenin tyrosine phosphorylation is reduced nearly fivefold with respect to control embryos. Conversely, tyrosine phosphorylation is significantly increased in dfergof embryos. Much less ß-catenin is recovered from dfergof embryos, suggesting that hyperphosphorylated ß-catenin is removed from AJs and degraded. This is confirmed by whole-mount staining of dfergof embryos, where the levels of ß-catenin are decreased in the epidermis of stage 13 embryos. DE-Cadherin levels may also be slightly reduced in stage 13 dfergof embryos, but the result is more variable. Western blots on total extracts from late stage dfergof embryos also show a reduction in the levels of ß-catenin (Murray, 2006),
A Drosophila gene (dfps85D) has been identified whose product resembles the proteins encoded by vertebrate fps/fes and the closely related gene fer. dfps85D is located at chromosomal position 85D10-13 and is unlikely to correspond to any previously defined genetic locus in Drosophila. Expression of the gene is entirely zygotic in origin and occurs throughout the life cycle. But hybridization in situ revealed that the pattern of expression is specialized and evolves in a provocative manner. The most notable feature of expression is the diversity of developmental periods, tissues, and cells in which it occurs. In some tissues, expression is transient; in others, it is continuous. Expression occurs in both mitotic and terminally differentiated tissue and, at various times in development, is prominent in imaginal disks, gut, muscle, testes, ovaries, retina, and other neural tissues. It appears that the use of dfps85D is more diversified than that of other Drosophila protein-tyrosine kinases reported to date and contrasts sharply with the restricted expression of fps itself in vertebrates (Katzen, 1991).
In situ hybridization revealed that dfps85D expression is first detectable at several positions in the late cellular blastoderm, including the yolk nuclei (vitellophages), where expression is especially strong and maintained into early gastrulation. Expression was also observed in dorsomedial, dorsolateral, and posterior positions. These regions encompass the anlage for the amnioserosa, dorsal epidermis, and proctodeum. During germ band extension, expression continues in the amnioserosa and the dorsal epidermis and becomes pronounced in the proctodeum. In the fully extended embryo, expression also appears in the ventral ectoderm, clypeolabrum, invaginating stomadeum, and mesoderm. Subsequent to germ band shortening, expression becomes more general but is still not universal. Sites of expression included the clypeolabrum, foregut, visceral mesoderm, somatic mesoderm, ventral epidermis, procephalic lobe, amnioserosa, and the dorsal ridge. Expression is notably absent from most of the developing nervous system, including the supraesophageal ganglia, the subesophageal ganglia, and the majority of lateral cell bodies of the ventral nerve cord. Expression is detected, however, in cells located at the midline of the ventral nervous system (Katzen, 1991).
In the final stages of embryogenesis, expression appears transiently in somatic muscle, pharyngeal muscles, tracheal epithelium, and spiracles and persistently in the frontal sac, esophagus, and proventriculus. In third-instar larvae, expression is detected in all imaginal disks. Transcripts were distributed unevenly within the disks and were especially prominent in the adepithelium. In the eye portion of the eye-antennal discs, expression is weak anterior to the morphogenetic furrow but becomes strong in both the apical and basal levels immediately posterior to the furrow; in more posterior positions, expression is predominantly in the basal portion of the tissue. Expression is also apparent in neural tissue, specifically the cellular cortices of the midbrain and ventral ganglia. Expression levels in the optic lobe are much lower and more discrete. Other tissues expressing dfps85D are the testes, immature blood cells of the lymph glands, and the polyploid epithelial cells of the midgut. There is no detectable expression in the ovaries or in the polyploid tissue of salivary glands, fat body, and larval muscles (Katzen, 1991).
The pattern of expression established in larvae persists into the early pupal stage but is supplemented by the appearance of expression in the tracheal epithelium and abdominal histoblasts and in precursors for visceral muscle. Later in pupal development, expression in most epithelial tissues diminishes appreciably but is prominent in developing skeletal muscle. Expression in muscle varies as development progresses. For example, 48 h into the pupal stage, expression is high in the direct flight muscles and low in the indirect flight muscles. Later, expression in both types of muscle is at the same low level (Katzen, 1991).
dfps85D is expressed in the developing testes throughout pupal development. Midway through the pupal period, expression declined to undetectable levels in the cortex of the midbrain but is strong in regions of the optic lobe. Subsequently, two distinct layers of the optic lamina expressed dfps85D strongly. The more distal hybridization (away from the brain, toward the eye) is located at the base of the lamina cellular cortex and is likely to represent expression from either the L4 or L5 cells. The more proximal expression is in cells located near the base of the lamina neuropile. Their location suggests that they are neuroglial cells. Also expressing dfps85D are a small group of cells of undetermined identity, located at the junction of the medulla, lobula, and lobula plate neuropiles (Katzen, 1991).
Expression in adult flies was especially strong in the retina, more so at the base than at the apex of the tissue, a layering that suggests expression in photoreceptor cells. The widespread expression detected in the thoracic muscles of pupae has now disappeared but is observed instead in the lateral tergosternal muscles of the abdomen. Expression continues in some regions of the testes and appears for the first time in the ovary, localized to the follicular epithelium, particularly at stages 10 to 11 of oogenesis. As in the larval gut, expression is detectable in the epithelium throughout the gut and in specific regions of the proventriculus. Expression is not detected in any portion of the adult brain (Katzen, 1991).
dfer expression is highly dynamic in a wide range of tissues, including the epidermis, central nervous system and developing trachea (Katzen, 1991). In the epidermis, dfer is strongly expressed in the leading edge cells, beginning at late stage 13 and continuing throughout dorsal closure to the end of stage 15. In the CNS, dfer is expressed in the midline glia at stage 13, and later in a segmentally repeated subset of cells and in the dMP2 neurons. To investigate the distribution and localisation of DFer protein, an antibody was raised against an N-terminal fragment of DFer that excludes the SH2 and kinase domains. This fragment overlaps the predicted protein for the intermediate isoform DFerRC by 30 residues. The antibody recognises ectopic expression of DFer-RB using the GAL4/UAS system, and staining is lost in the dferΔex1 mutant, which confirms the specificity of the antibody (Murray, 2006),
DFer protein is ubiquitously expressed at relatively uniform levels throughout embryogenesis. Prior to dorsal closure, during stages 9-10, DFer is predominantly localised to the cytoplasm, although some weak staining is seen around the perimeter of epidermal cells. During stages 11-12, DFer becomes localised to cell-cell junctions in the epidermis. DFer becomes polarised in the leading edge cells as dorsal closure proceeds, as is seen for several other cell-cell junction proteins (e.g. Canoe). Although initially present around the entire circumference of the cell, DFer is lost from the border with the amnioserosa during stages 13-14. DFer protein is also apically enriched in other epithelial sheets such as the gut and trachea, and is expressed in a subset of cells within the CNS (Murray, 2006),
In vertebrates, Fer associates with the adherens junction components p120-catenin and ß-catenin (Kim, 1995; Rosato, 1998). To test whether DFer also localises to adherens junctions, embryos were co-stained for DFer and DE-Cadherin (Drosophila E-Cadherin). In the dorsal epidermis, DFer extensively colocalises with DE-Cadherin, although the distribution is not identical. At the leading edge, DE-Cadherin can be seen around the apical circumference at stage 14, whereas at this stage DFer is lost from the leading edge itself. In the amnioserosa, DFer is only occasionally detected at cell-cell junctions, where again it colocalises with DE-Cadherin. At the leading edge, DFer is apical to the more basal septate junction proteins, Fasciclin 3 and Discs large (Murray, 2006),
Expression of DFer in leading edge cells suggests that it might play a role in dorsal closure. In the GAL4 insertion line MZ465, a P-element has inserted upstream of the first, non-coding, exon of dfer. Mutations in dfer were generated by imprecise excision of the P-element and by male recombination, and screened for loss of DFer protein expression. Nine recombinant lines were generated. In one line, dferΔex1, the deletion removes only the promoter and first exon of the dfer gene. In the other eight lines, a region of over 50 kb is deleted, encompassing the entire dfer locus and the four genes proximal to dfer (CG8129, a threonine dehydratase; CG18473, a phosphotriesterase; CG33936, a zinc finger protein; and CG33937). One of these lines, Df(3R)dferΔ1 (hereafter dferΔ1), was selected for further analysis. Both dferΔ1 and dferΔex1 still express functional GAL4 in patterns similar to that of MZ465. dferΔ1 homozygotes are embryonic lethal in 53% of cases with the remainder dying during larval and pupal development. dferΔex1 homozygotes are both viable and fertile. All results in this study using dferΔex1 are from embryos derived from dferΔex1 homozygous parents (Murray, 2006),
dferΔ1 is an RNA and protein null for all DFer isoforms. In dferΔex1 mutants, dfer mRNA is lost from the CNS and leading edge, but tracheal expression is still evident, as is a low level of ubiquitous staining in the epidermis. DFer protein is not detected in the CNS, but some cell-cell junction staining is faintly visible in the epidermis. The first, non-coding, exon and promoter are deleted in dferΔex1 mutants; however, mRNA transcripts starting at the second exon, which encodes the translational start, are present. Western blots show that full-length DFer protein is produced in dferΔex1 mutants. Thus, dferΔex1 is a hypomorphic mutation in which dfer mRNA expression is lost in a subset of tissues and DFer protein levels in the dorsal epidermis are reduced (Murray, 2006),
During dorsal closure in wild-type embryos, the leading edge and neighbouring cells elongate along the dorsoventral axis. The profile of the leading edge changes from an irregular scalloped to a straightened edge as the actomyosin contractile cable forms. Phosphotyrosine (P-Tyr) levels increase along the leading edge, particularly at the contact points between neighbouring cells or actin nucleating centres (ANC). As closure continues, leading edge cells extend filopodial and lamellipodial processes that zip up the epidermal sheets that meet at the dorsal midline (Murray, 2006),
In dferΔ1 mutants, the actomyosin cable is reduced and the leading edge maintains an irregular profile during closure. P-Tyr levels at the leading edge are also decreased, consistent with the loss of a cytoplasmic tyrosine kinase. These morphological differences are accompanied by a slower rate of closure. In wild-type embryos, dorsal closure is complete by the end of stage 15. dferΔ1 mutant embryos are still open dorsally three hours later, at the end of stage 16. Closure eventually completes, although 2% of cuticles from dferΔ1 mutants exhibit an anterior hole. By contrast, dferΔex1 mutants appear to close normally and exhibit normal leading edge morphology, F-actin and P-Tyr staining (Murray, 2006),
Vertebrate Fes/Fer kinases and members of the Src family kinases share some substrates, such as p120ctn, ß-catenin (Piedra, 2003) and the Arp2/3 activator Cortactin (Kim, 1998; Wu, 1993), and play similar roles in regulating cell-cell adhesion. Src family kinases are functionally redundant in several developmental processes, including dorsal closure: single mutations in Src42A, tec29A and Src64C do not exhibit dorsal holes, whereas double mutants, such as tec29A,Src42A, do. Therefore, whether Src42A and DFer act together in dorsal closure was tested (Murray, 2006),
Src42A single mutants do not exhibit dorsal holes, but show defects in mouthpart formation and epithelial organisation following closure. Src42A embryos also exhibit defects in leading edge cells that are similar to, but less severe than, dferΔ1 mutants: the actomyosin cable is disrupted, P-Tyr staining is weaker than in wild type, and dorsal closure is slightly defective. Eight percent of embryos show a very small dorsal hole at late stage 16 when analysed by confocal microscopy, and the remainder show an irregular arrangement of epidermal cells that is reflected later in the arrangement of dorsal hairs. Embryonic lethality is 63%, with 60% of the unhatched embryos showing malformed mouthparts and a small anterior hole (Murray, 2006),
When the Src42A and dferΔex1 mutants are combined, leading edge cells have a more irregular profile and P-Tyr staining is weaker. When analysed by confocal microscopy, most embryos are still undergoing dorsal closure by late stage 16. Embryonic lethality is 100%, and embryos have breaks and irregularities in the dorsal hair pattern, and a small anterior hole near the mouthparts. In the remaining embryos, dorsal closure fails completely, leaving a large anterior hole. When the dfer deficiency, dferΔ1, and Src42A are combined, these defects are further enhanced. The leading edge becomes highly irregular with a complete loss of the F-actin cable and a substantial reduction in P-Tyr staining. When analysed by confocal microscopy, embryos exhibit a large dorsal hole at late stage 16. Cuticle preparations from these embryos show a large anterior hole (30%) or a small anterior hole (59%), often with small scabs along the dorsal midline. The remaining embryos do not secrete a cuticle (11%). Therefore, when either DFer or Src42A expression is reduced, leading edge cell morphology is compromised and closure is delayed, but when both are removed dorsal closure fails completely (Murray, 2006),
Fes/Fer family non-receptor tyrosine kinases were first identified as the retroviral oncogenes, v-fps and v-fes, from avian and feline sarcomas, respectively (Shibuya, 1980; Snyder, 1969). In v-fes and v-fps, a fragment of the viral GAG protein is fused to the N terminus of the endogenous protein. The N terminus of Fes/Fer is implicated in the regulation of autophosphorylation (Orlovsky, 2000), and N-terminal fusions result in a constitutively active kinase. Activated kinases have also been created by the introduction of an N-terminal myristoylation sequence (Greer, 1994), and by point mutations in the first coiled-coil domain (Cheng, 2001). These are thought to disrupt intramolecular autoregulatory interactions (Murray, 2006),
A third dfer mutant, dfergof, was isolated that behaves as a gain-of-function mutant. Homozygous dfergof mutants are embryonic lethal and exhibit a number of embryonic defects, including a large dorsal hole and an aberrant midline crossing of axons in the CNS. DFer protein is expressed at higher levels than in wild-type embryos, and when the levels of DFerRB are further increased in dfergof mutants, the midline-crossing defect is enhanced. By contrast, expression of DFerRB in a wild-type background has no effect on dorsal closure or CNS development. dfergof mutants express an N-terminally modified form of DFerRB, similar to the activated forms of Fes/Fer kinases, such as v-fps. This appears as an extra band, slightly larger than the canonical DFer isoform (Murray, 2006),
In dfergof mutants, dorsal closure starts to arrest at stage 13, with only the most anterior and posterior segments meeting at the dorsal midline at stage 16. The leading edge and dorsal epidermal cells fail to elongate. The actomyosin cable still forms and creates a straightened leading edge, albeit one reduced in thickness. The F-actin-rich filopodia that extend from the leading edge are also much less extensive (Murray, 2006),
The amnioserosa is also affected in dfergof mutant embryos. In wild-type embryos, F-actin staining becomes increasingly strong at the perimeter of amnioserosal cells as they progressively contract. In dfergof mutants, F-actin staining is much less concentrated at cell-cell junctions, and the cell cortices are irregular. Accelerated contraction of isolated amnioserosal cells still occurs (Murray, 2006),
To characterise further dfergof mutants, GFP-actin was expressed ubiquitously in wild-type and dfergof backgrounds. The leading edge actomyosin cable and filopodia are reduced in dfergof mutants, and less GFP-Actin is concentrated at the cell-cell junctions of amnioserosal cells. In addition, the amnioserosal cells exhibit more lamellipodia (Murray, 2006),
In dfergof mutants the P-element, pGawB, has undergone a rearrangement, duplicating and inverting the GAL4 gene, deleting pBluescript, and all but the promoter and first exon of the mini-white gene. As predicted from this map, dfergof still expresses GAL4. In fact, GAL4 is expressed at higher levels and in more tissues, such as the epidermis and the amnioserosa, than in the original starting line, GAL4MZ465. Three new fusion transcripts were detected in which the first exon of the mini-white gene is spliced to the beginning of the second exon of dfer, (wex1-DFerRB), to the beginning of the third exon (wex1_stop1), or to an alternate splice acceptor in intron2 (wex1_stop2). The second and third of these transcripts encode short proteins comprising the first 24 residues of White, followed shortly thereafter by stop codons. The first transcript encodes a predicted fusion protein in which the first 24 residues of White (MGQEDQELLIRGGSKHPSAEHLNN) are followed by 12 novel amino acids (RAATQIGSNESI) and the entire DFerRB protein. This chimaeric protein is strikingly similar to the oncogenic forms of Fes, such as the Fujinami sarcoma virus protein GAG-Fps (Shibuya, 1980) , in which part of the retroviral GAG sequence is fused to the N terminus of the entire Fps gene (Murray, 2006),
Reference names in red indicate recommended papers.
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date revised: 10 December 2006
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