armadillo: Biological Overview | Evolutionary Homologs | Regulation | Protein Interactions | Developmental Biology | Effects of Mutation | References
Gene name - armadillo
Cytological map position - 2B15
Function - cytoskeletonal element
Symbol - arm
Genetic map position - 1-[0.4]
Classification - plakoglobin homolog
Cellular location - sub-surface
|Recent literature||Balmer, S., Dussert, A., Collu, G. M., Benitez, E., Iomini, C. and Mlodzik, M. (2015). Components of intraflagellar transport Complex A function independently of the cilium to regulate canonical Wnt signaling in Drosophila. Dev Cell 34: 705-718. PubMed ID: 26364750
The development of multicellular organisms requires the precisely coordinated regulation of an evolutionarily conserved group of signaling pathways. Temporal and spatial control of these signaling cascades is achieved through networks of regulatory proteins, segregation of pathway components in specific subcellular compartments, or both. In vertebrates, dysregulation of primary cilia function has been strongly linked to developmental signaling defects, yet it remains unclear whether cilia sequester pathway components to regulate their activation or cilia-associated proteins directly modulate developmental signaling events. To elucidate this question, an RNAi-based screen was conducted in Drosophila non-ciliated cells to test for cilium-independent loss-of-function phenotypes of ciliary proteins in developmental signaling pathways. The results show no effect on Hedgehog signaling. In contrast, the screen identified several cilia-associated proteins as functioning in canonical Wnt signaling. Further characterization of specific components of Intraflagellar Transport complex A uncovered a cilia-independent function in potentiating Wnt signals by promoting β-catenin/Armadillo activity.
|Hall, E. T. and Verheyen, E. M. (2015). Ras-activated Dsor1 promotes Wnt signaling in Drosophila development. J Cell Sci. [Epub ahead of print]. PubMed ID: 26542023
Wnt/Wingless (Wg) and Ras/MAPK signaling both play fundamental roles in growth, cell-fate determination, and when dysregulated, can lead to tumorigenesis. Several conflicting modes of interaction between Ras/MAPK and Wnt signaling have been identified in specific cellular contexts, causing synergistic or antagonistic effects on target genes. This study found novel evidence that the dual specificity kinase Downstream of Raf1 (Dsor1), also known as MEK. is required for Wnt signaling. Knockdown of Dsor1 results in loss of Wingless target gene expression, as well as reductions in stabilized Armadillo (Arm; Drosophila beta-catenin). A close physical interaction was found between Dsor1 and Arm; catalytically inactive Dsor1 causes a reduction inactive Arm. These results suggest that Dsor1 normally counteracts the Axin-mediated destruction of Arm. Ras-Dsor1 activity is independent of upstream activation by EGFR, rather it appears to be activated by the insulin-like growth factor receptor to promote Wg signaling. Together our results suggest novel crosstalk between Insulin and Wg signaling via Dsor1.
|Franz, A., Shlyueva, D., Brunner, E., Stark, A. and Basler, K. (2017). Probing the canonicity of the Wnt/Wingless signaling pathway. PLoS Genet 13(4): e1006700. PubMed ID: 28369070
The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the β-catenin/TCF complex. Several studies have proposed alternative interaction partners for β-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. This study examined, on a genome-wide scale, the requirement for Armadillo (Arm, Drosophila β-catenin) and Pangolin (Pan, Drosophila TCF) in the Wnt/Wingless(Wg)-induced transcriptional response of Drosophila Kc cells. Using somatic genetics, it was demonstrated that both Arm and Pan are absolutely required for mediating activation and repression of target genes. Furthermore, by means of STARR-sequencing Wnt/Wg-responsive enhancer elements were identified and it was found that all responsive enhancers depend on Pan. Together, these results confirm the dogma of canonical Wnt/Wg signaling and argue against the existence of distal pathway branches in this system.
|Zhang, T., Hsu, F. N., Xie, X. J., Li, X., Liu, M., Gao, X., Pei, X., Liao, Y., Du, W. and Ji, J. Y. (2017). Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids. Proc Natl Acad Sci U S A 114(36): E7469-e7478. PubMed ID: 28827348
Deregulated Wnt signaling and altered lipid metabolism have been linked to obesity, diabetes, and various cancers, highlighting the importance of identifying inhibitors that can modulate Wnt signaling and aberrant lipid metabolism. This study has established a Drosophila model with hyperactivated Wnt signaling caused by partial loss of axin, a key component of the Wnt cascade. The Axin mutant larvae are transparent and have severe adipocyte defects caused by up-regulation of beta-catenin transcriptional activities. This study demonstrates pharmacologic mitigation of these phenotypes in Axin mutants by identifying bortezomib and additional peptide boronic acids. The suppressive effect of peptide boronic acids on hyperactive Wnt signaling is dependent on alpha-catenin; the rescue effect is completely abolished with the depletion of alpha-catenin in adipocytes. These results indicate that rather than targeting the canonical Wnt signaling pathway directly, pharmacologic modulation of beta-catenin activity through alpha-catenin is a potentially attractive approach to attenuating Wnt signaling in vivo.
|Kaur, P., Saunders, T. E. and Tolwinski, N. S. (2017). Coupling optogenetics and light-sheet microscopy, a method to study Wnt signaling during embryogenesis. Sci Rep 7(1): 16636. PubMed ID: 29192250
Optogenetics allows precise, fast and reversible intervention in biological processes. Light-sheet microscopy allows observation of the full course of Drosophila embryonic development from egg to larva. Bringing the two approaches together allows unparalleled precision into the temporal regulation of signaling pathways and cellular processes in vivo. To develop this method, this study investigated the regulation of canonical Wnt signaling during anterior-posterior patterning of the Drosophila embryonic epidermis. Cryptochrome 2 (CRY2) from Arabidopsis Thaliana was fused to mCherry fluorescent protein and Drosophila beta-catenin to form an easy to visualize optogenetic switch. Blue light illumination caused oligomerization of the fusion protein and inhibited downstream Wnt signaling in vitro and in vivo. Temporal inactivation of beta-catenin confirmed that Wnt signaling is required not only for Drosophila pattern formation, but also for maintenance later in development. We anticipate that this method will be easily extendable to other developmental signaling pathways and many other experimental systems.
|Roper, J. C., Mitrossilis, D., Stirnemann, G., Waharte, F., Brito, I., Fernandez-Sanchez, M. E., Baaden, M., Salamero, J. and Farge, E. (2018). The major beta-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo. Elife 7. PubMed ID: 30024850
In vivo, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. This study finds the molecular stretching of the highly conserved Y654-beta-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the beta-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45% stretching between the two alpha-helices linked by the site and a 15% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating Drosophila embryos. This is followed by the predicted release of 16% of beta-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the beta-catenin pathway process.
Armadillo and alpha-Catenin are components of a multiprotein complex that both maintains and initiates formation of sheets of epithelial cells. These proteins are part of the adherens junction, a biochemical crossroad where cells are attached one to another, and signals that adhesion has taken place are communicated to the interior of cells. The proteins anchor the adherens junction to the actin cytoskeleton, thus connecting surface and interior, providing them with contractile function.
Armadillo can reversably associate with the adherens junction; that is, it can take up with it, or leave it alone. The cytoplasmic localization of ARM is regulated by phosphorylation, the attachment of a phosphate residue to a protein using kinase enzymes. This is the main mechanism of the cell for intermolecular communication. Zeste-white 3, a serine threonine kinase, lies upstream of ARM, and positively regulates the phosphorylation of ARM. Tyrosine phosphorylation modifies the adherens junction, increases the level of cytoplasmic rather than junctional ARM, but probably does not result in disassembly of the junction. Wingless signal negatively regulates ARM phosphorylation (Heifer, 1994). The role of Wingless in cell adhesion, cell boundary formation, cell mobility and gene expression is currently viewed via glimpses of incomplete yet tantalizing information (Peiper, 1994a and b).
How do wingless signals get to the nucleus? The pathway has now been worked out in Drosophila based on studies with vertebrates. A component of the wingless pathway has been identified in Xenopus. A maternally expressed Xenopus homolog of mammalian HMG box factors (XTcf-3) binds to ß-catenin, the vertebrate homolog of Armadillo. XTcf-3 (Drosophila homolog: Pangolin) is a transcription factor that mediates ß-Catenin-induced axis formation in Xenopus embryos. It is proposed that the ßcatenin-XTcf-3 complex is responsible for activation of targets genes in response to upstream Wnt signals that allow cytoplasmic ß-catenin to interact with XTcf-3 (Molenaar, 1996). These observations suggest that Armadillo, plus the associated transcription factor, Pangolin, are the nuclear affectors of Wingless.
An extensive screen has been carried out to identify genes interacting with Armadillo. Two viable fly stocks have been generated by altering the level of Armadillo available for signaling. Flies from one stock overexpress Armadillo (Armover) and, as a result, have increased vein material and bristles in their wings. Flies from the other stock have reduced cytoplasmic Armadillo following overexpression of the intracellular domain of Drosophila E-cadherin (Armunder). These flies display a wing-notching phenotype typical of wingless mutations. Both misexpression phenotypes can be dominantly modified by removing one copy of genes known to encode members of the wingless pathway. This study identifies and describes further mutations that dominantly modify the Armadillo misexpression phenotypes. These mutations are in genes encoding three different functions: establishment and maintenance of adherens junctions, cell cycle control, and Egfr signaling (Greaves, 1999).
Mutations in 17 genes (26 deficiencies) were characterized that interact with Armover and/or Armunder. Interaction strength varies from deficiency to point mutation, suggesting that several genes in the original deficiencies could have contributed to, or modified, the interaction. Only for 7 of the 17 genes have interactions been identical between the point mutation and the corresponding starting deficiency. The 17 genes were sorted into four groups described below.
The candidate gene approach does not always yield an interaction. For example, two obvious candidates uncovered by an interacting deficiency on chromosome II, Kelch and cadherin-N, do not modify either Arm misexpression phenotype (the deficiency modifies both). The lack of interaction with cadherin-N is particularly surprising considering the high degree of homology of its intracellular domain with that of E-cadherin . Ultimately, there remain 28 deficiencies without a mutant that could account for the interaction (this includes the Kelch/cadherin-N deficiency). These map to 10 overlapping chromosomal regions. Testing smaller deficiencies further refines the chromosomal location of each interactor. Once a small interacting region was identified, P-element-induced mutations were obtained and tested for an interaction with Armover and Armunder. This approach identified six P-element-induced mutations that modify the Arm wing phenotypes in a manner similar to the original deficiencies. All enhance Armover and suppress Armunder, both in the eye and the wing. These interactions are similar to those with sgg/zw3, which encodes a negative regulator of Armadillo levels. An interacting P insertion mutates fasciclin3 and yet another insertion disrupts twins. The remaining four are in genes not yet cloned (Greaves, 1999).
Among the interactors identified was naked (nkd), a mutant that has long been associated with excess Wg activity. The embryonic phenotype of nkd mutants is characterized by an excess of naked cuticle, just like that of sgg/zw3 mutants or embryos overexpressing Wg. In the case of sgg/zw3, this phenotype clearly follows from overactivation of the pathway, irrespective of whether endogenous wg is present or not. In contrast, wg/nkd double mutants resemble the wg single mutant, suggesting that nkd is upstream of wg. More precisely, since nkd mutants have enlarged stripes of Engrailed [and concomitant Hh] expression, nkd has been proposed to be a negative regulator of Engrailed expression. Broader hh expression in nkd embryos (as a result of widened engrailed expression) is thought to induce ectopic stripes of wg expression; this would cause the naked cuticle phenotype. However, in wing imaginal discs, wg expression is not controlled by engrailed or hh and therefore the finding that nkd modifies the Armover and Armunder phenotypes in the wing implies a more widespread role of nkd in Wg signaling. Maybe absence of nkd function renders cells more responsive to Wg. This would explain why endogenous Wg is required for the nkd phenotype to arise. It would also be consistent with the genetic interactions that are detected in the wing. Note that, so far, no function has been ascribed to nkd in disc development (Greaves, 1999).
The screen identified several genes involved in the assembly or maintenance of adherens junctions. shotgun (encoding DE-cadherin) itself is not very illuminating since it is expected that the phenotype caused by an excess of intracellular cadherin domain will be suppressed by decreasing endogenous cadherin levels. Still, this interaction shows that the level of overexpression afforded by the Gal4p system is within physiological levels. Interaction with fat and dachsous suggests that these two nonclassical cadherins interact (maybe directly) with Arm. Initial analysis of the intracellular domain of Fat and Dachsous fail to identify an Arm/ß-catenin binding site homologous to that found in E-cadherin. However, subsequent sequence examination suggests the existence of a bipartite site. Genetic interactions with fat and dachsous strongly suggest that this proposed site is functional, and thus removing one copy of the fat or dachsous gene would release additional Arm to the cytoplasm and make it available for use in Wg transduction. Interactions with fat and dachsous in the eye confirm the ability of these genes to modify cytoplasmic Arm levels. It also indicates that these genes are expressed in the eye and may be functional there (Greaves, 1999).
Cadherin-N (CadN) binds to Arm. Therefore the failure of CadN to interact in this screen suggests that CadN may not be expressed to significant levels in the posterior compartment of wing imaginal discs or in eye precursors. In contrast, crumbs (crb) and stardust (sdt) do interact. The proteins encoded by these genes are not thought to participate in junctional complexes per se. Rather, they control the biogenesis of the junctions. It is suggested that decreasing the activity of crb or sdt has a quantitative effect on the number or size of adherens junctions and this would lead to more Arm being released from the membrane and made available for Wg signaling (Greaves, 1999).
The interaction with discs-large (dlg) is somewhat surprising since DLG is presumed to act in septate junctions. DLG localizes at septate junctions once adherens junction contacts are established. However, ZO-1, the vertebrate homolog of Dlg, has been shown to interact with ß-catenin. The genetic interaction of dlg with Armover and Armunder implies either that Dlg binds Arm in vivo, or that altering Dlg levels affects septate junctions, which in turn are needed for the stability of adherens junctions. In support for the latter alternative the dlgM52 mutation leads to disruption not only of septate but also adherens junctions. In fact, in dlgM52 mutants, Arm no longer localizes to the membrane. This could lead to increased Arm in the cytoplasm (Greaves, 1999).
The interactions with genes encoding components of the Egf pathway were initially dismissed because argos and Egfr, which have opposite effects on the Egf pathway, interact similarly with Armunder and Armover. However, recent work has demonstrated an antagonism between the Wg and Egf pathways in the embryonic epidermis. This antagonism is probably not universal since another embryonic function of Wg, the maintenance of Engrailed expression, is not affected by Egf signaling. However, the interactions that were uncovered in the wing suggest that the Egf-Wg antagonism may not be limited to cuticle patterning. It is noteworthy that, in the wing, only an interaction with Armover (which involves ectopic bristles) was seen. It may thus be that Wg and Egf only compete at places where specialized cuticular structure are formed, although, while denticles are negatively regulated by Wg, bristles are made in response to Wg signaling. No explanation is available as to why argos, a negative regulator of Egf signaling, should interact in the same manner as Egfr (Greaves, 1999).
Genes encoding cell cycle components also interact with Arm misexpression lines; this was unexpected. However, recent work by others has established a link between Wg and the cell cycle. At the wing margin of the anterior compartment, wg suppresses string (stg) transcription via induction of the proneural genes achete (ac) and scute (sc). This is followed by G2 arrest and the formation of specialized sensory bristles. In the posterior compartment no such G2 arrest takes place, and therefore there is no simple explanation as to why stg should enhance the number of ectopic noninnervated bristles induced by excess wg signaling. This and the finding that stg suppresses the Armunder phenotype implies that somehow loss of stg activity potentiates Wg signaling (Greaves, 1999).
Work in both fruit flies and vertebrates has hinted at the central role played by Arm/ß-catenin in many cellular functions, most notably, Wg signaling, cell adhesion, and, more recently, Egf signaling and the cell cycle. It is expected that the characterization of the P-induced mutations identified during the screen described here will broaden the perspective on Arm function. It is encouraging that one such P has been inserted in a gene that has previously been implicated in cell adhesion (fasciclin3). The interaction with twins (tws), a regulatory subunit of protein phosphatase 2A (PP2A), is also promising. A vertebrate regulatory subunit of PP2A has recently been shown to regulate ß-catenin activity. It will be interesting, therefore, to determine if Arm, Apc, or Axin are substrates of PP2A. It is hoped that further experiments with tws and fas3, as well as the characterization of the remaining four mutants, will help an understanding of how diverse functions like cell adhesion and cell cycle and signaling might be integrated by the usage of one common component, Arm (Greaves, 1999).
The final step in morphogenesis of the adult fly is wing maturation, a process not well understood at the cellular level due to the impermeable and refractive nature of cuticle synthesized some 30 h prior to eclosion from the pupal case. Advances in GFP technology now make it possible to visualize cells using fluorescence after cuticle synthesis is complete. Between eclosion and wing expansion, the epithelia within the folded wing begin to delaminate from the cuticle and that delamination is complete when the wing has fully expanded. After expansion, epithelial cells lose contact with each other, adherens junctions are disrupted, and nuclei become pycnotic. The cells then change shape, elongate, and migrate from the wing into the thorax. During wing maturation, the Timp gene product, tissue inhibitor of metalloproteinases, and probably other components of an extracellular matrix are expressed that bond the dorsal and ventral cuticular surfaces of the wing following migration of the cells. These steps are dissected using the batone and Timp genes and ectopic expression of αPS integrin, inhibitors of Armadillo/β-catenin nuclear activity and baculovirus caspase inhibitor p35. It is concluded that an epithelial-mesenchymal transition is responsible for epithelial delamination and dissolution (Kiger, 2007; full text of article).
The following outline is proposed of that program based upon cell behavior: delamination and severing contacts; changing cell shape; and migration and ECM synthesis.
Stage 1, delamination and severing contacts
A signaling role for integrins during the prepupal apposition has been proposed that prepares cells for integrin-based adhesion of the epithelia at the pupal apposition. The observation that wing epithelial cells persist in the blistered regions produced by ectopic αPS integrin expression suggests that the integrin interaction also prepares cells to respond to the later signal that induces epithelial delamination and dissolution. This signal is also blocked in the mutant batone, which prevents wing expansion. Some cells begin to delaminate from the cuticle before wing expansion has begun, and all have delaminated by the time expansion is complete. Delamination must involve severing of ECM contacts. The precision of the cellular array in a newly open wing must derive from cell–cell contacts between stretched cells that are maintained following delamination. Each cell then compacts and becomes round (as judged by the increase in fluorescence intensity). The round cells have evidently severed their junctions with adjacent cells because the precise array of cells begins to break up and Arm-GFP moves from the cell membrane to the cytoplasm (Kiger, 2007).
It would appear that disturbing the normal state of Arm/β-catenin signaling activity in epithelial cells blocks delamination. Delamination is blocked by ectopic expression of Pygo in the epithelial cells, which blocks expression of Arm target genes in a variety of tissues, and by ectopic expression of Shaggy, which blocks expression of Arm target genes by phosphorylating cytoplasmic Arm, promoting its degradation and depleting nuclear Arm. Ectopic expression of stabilized forms of Arm not subject to Shaggy phosphorylation evidently has a dominant-negative effect on Arm signaling activity in the maturing wing, blocking delamination of epithelial cells. This interpretation is supported by the following observations. First, no effect is produced by ectopic expression of wild-type Arm using the same Gal4-30A driver, consistent with other reports, very likely indicating the efficiency with which wild-type Arm is eliminated by phosphorylation and degradation through the proteasome. Second, a very low level of nuclear Arm is sufficient for target gene expression. The Arm-GFP fusion protein used here is fully active and completely covers homozygosity for a null arm allele, yet nuclear Arm-GFP cannot be detected in cells receiving a Wingless signal. Thus, it is reasonable that non-physiologically high levels of stable forms of Arm could have a dominant-negative effect, not unlike the inhibitory effect of over-expression of Pygo on Arm-directed transcription. (Kiger, 2007).
Arguing against an interpretation that the effects of ectopic gene expression might be non-specific, note that Gal4-30A-driven expression of p35 does not block delamination. Nor does Gal4-30A-driven expression of either αPS integrin or wild-type transcription factor Pangolin/dTCF/LEF-1, or a dominant-negative form of CREB have any effect on wing maturation (Kiger, 2007).
Stage 2, changing cell shape
The round cells then begin to change shape, extending thin cytoplasmic filaments, and elongate into spindles that associate with similarly shaped cells forming streams. The fact that p35 expression interrupts developmental progression at the round cell stage clearly separates Stage 1 from the changes in cell shape, cell migration, and ECM synthesis events that follow. In some cellular contexts caspase inhibition prevents cell migration independently of blocking apoptosis. It has been shown that the nuclei of wing cells cease to retain nuclear-targeted GFP and begin to fragment their DNA at what appears to be the round cell stage, consistent with the observation of pycnotic nuclei at this stage (Kiger, 2007).
Stage 3, migration and ECM synthesis
The cells migrate toward the hinge and into the body of the fly, leaving behind components, perhaps including tissue inhibitor of metalloproteinases, of an ECM that will bond dorsal and ventral cuticular surfaces. It is noteworthy that Timp deficiency does not interfere with cell migration. ECM assembly must be the final step in the developmental program. The nonautonomous action of Timp in bonding cuticle secreted by mutant Timp clones suggests that Timp is present in abundance and diffuses over large distances in the wing to participate in ECM formation (Kiger, 2007).
Precisely how ectopic expression of the various UAS transgenes studied in this paper produces wing blisters or collapsed wings is not wholly clear. It seems doubtful that cells that fail to delaminate during early phases of tissue remodeling would secrete ECM components normally. Yet a variable number of cells in these wings do delaminate and leave the wing, presumably because of variation in the level of Gal4-30A expression. These cells might be expected to secrete the necessary ECM components, although the level of critical component(s) may be insufficient for normal bonding to occur in some cases. Blister formation might also be caused by the presence of numbers of undelaminated cells physically preventing ECM from bonding the underlying cuticle. Note that when ectopic p35 expression is limited, a moderate number of round, delaminated cells can become bound in the wing without producing blisters (Kiger, 2007).
The presence of true hemocytes in the wing raises the question of whether these cells play a role in wing maturation. If Gal4-30A was to be expressed in these cells, as well as in epithelial cells, interpretation of ectopic expression studies would be complicated. No cells were detected expressing DsRedGFP fluorescence that did not express ywing-GFP fluorescence, suggesting that Gal4-30A is not expressed in true hemocytes. The observations that Hemese-Gal4-driven expression of Shaggy or of Pygo has no effect on wing maturation strongly suggest that the effects of Shaggy and Pygo on wing maturation are not mediated by true hemocytes exclusively, if at all. While the possibility that Timp and/or other ECM components are supplied by true hemocytes cannot be ruled out, the bulk of the evidence supports an active role for epithelial cells in bonding the wing surfaces. Precocious death of epithelial cells induced by Gal4-30A-driven expression of Ricin A in late pupal epithelial cells prevents bonding of dorsal and ventral cuticle after eclosion. Because the wing cuticle is fully formed, the induced cell death must have occurred after cuticle deposition but before eclosion. UV irradiation after eclosion blocks both epithelial cell delamination and bonding of the wing surfaces. In addition, it is clear that mitotic clones of defective epithelial cells affect bonding of the wing surfaces. Mitotic clones mutant for an integrin gene produce blisters in the wing cuticle as do mitotic clones ectopically expressing PKAc (Kiger, 2007).
These studies describe for the first time the developmental program that completes morphogenesis of the adult fly. The requirement for a normal state of Arm/β-catenin signaling activity suggests that an epithelial–mesenchymal transition (EMT) transforms epithelial cells into mobile fibroblasts in the wing (Kiger, 2007).
The best known example of an EMT in Drosophila is neuroblast delamination. In embryonic central nervous system formation, Wingless signaling has been shown to induce nonautonomously the delamination of specific neuroectoderm cells to form S2 neuroblasts. In peripheral nervous system formation, Wingless signaling is required for bristle formation at the wing margin, and ectopic expression of Wingless induces ectopic bristles in the wing blade. The ability of Wingless to induce neuroectoderm cells to form neuroblasts is tightly regulated by Notch in both the central and peripheral nervous systems. Evidence supports the idea that Notch modulates Wingless signaling by associating directly with Arm/β-catenin to regulate its transcriptional activity (Kiger, 2007).
Arm/β-catenin signaling appears to be characteristic of EMTs. Translocation of Arm/β-catenin into the nucleus precedes gastrulation in Drosophila, the sea urchin, and zebrafish. EMTs occur in the vertebrate neural crest when cells delaminate from the neural epithelium and migrate throughout the embryo. In the avian neural crest, dominant-negative forms of β-catenin and LEF/TCF inhibit delamination of cells from the epithelium, G1/S transition, and transcription of target genes. β-Catenin and LEF/TCF proteins are observed to translocate to the nuclei of avian neural crest cells only during delamination and to be absent during advanced stages of migration. EMTs are also a characteristic of cancer formation and can be initiated in some cancers by aberrant β-catenin activity (Kiger, 2007).
Multiple ways of activating Arm/β-catenin signaling exist. There are two independently regulated pathways that can target Arm/β-catenin to the proteasome, the Shaggy/Glycogen synthase kinase 3 degradation complex and the Seven in Absentia Homologue/ubiquitin ligase degradation complex. Multiple G-protein-coupled receptors target the Shaggy/Glycogen synthase kinase 3 degradation complex for inhibition. Further studies are necessary to identify the hormone(s), receptor(s) and signal transduction mechanisms acting in the wing maturation program and to relate this work to the extensive studies of the hormonal signals controlling wing expansion and cuticle tanning (Kiger, 2007).
ARM has an N-terminal acidic region that is 43% homologous to human Plakoglobin, 13 central copies of a 42 amino acid repeat that is 70% identical to Plakoglobin, and a C-terminal glycine proline rich region 36% homologous to Plakoglobin (Peiper, 1990).
Beta-catenin binds to cadherins, Tcf-family transcription factors, and the tumor suppressor gene product Adenomatous Polyposis Coli (APC). A core region of beta-catenin, composed of 12 copies of a 42 amino acid sequence motif known as an armadillo repeat, mediates these interactions. The three-dimensional structure of a protease-resistant fragment of beta-catenin containing the armadillo repeat region has been determined. The 12 repeats form a superhelix of helices that features a long, positively charged groove. Although unrelated in sequence, the beta-catenin binding regions of cadherins, Tcfs, and APC are acidic and are proposed to interact with this groove (A. H. Huber, 1997).
date revised: 2 January 2000
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