Gene name - shotgun
Synonyms - DE-cadherin
Cytological map position - 57B13-14
Function - cell adhesion
Symbol - shg
Genetic map position -
Classification - E-cadherin
Cellular location - surface transmembrane protein
|Recent literature||Houssin, E., Tepass, U. and Laprise, P. (2015) Girdin-mediated interactions between cadherin and the actin cytoskeleton are required for epithelial morphogenesis in Drosophila Development 142: 1777-1784. PubMed ID: 25968313
E-cadherin-mediated cell-cell adhesion is fundamental for epithelial tissue morphogenesis, physiology and repair. E-cadherin is a core transmembrane constituent of the zonula adherens (ZA), a belt-like adherens junction located at the apicolateral border in epithelial cells. The anchorage of ZA components to cortical actin filaments strengthens cell-cell cohesion and allows for junction contractility, which shapes epithelial tissues during development. This study reports that the cytoskeletal adaptor protein Girdin physically and functionally interacts with components of the cadherin-catenin complex during Drosophila embryogenesis. Fly Girdin is broadly expressed throughout embryonic development and enriched at the ZA in epithelial tissues. Girdin associates with the cytoskeleton and co-precipitates with the cadherin-catenin complex protein alpha-Catenin (alpha-Cat). Girdin mutations strongly enhance adhesion defects associated with reduced DE-cadherin (DE-Cad) expression. Moreover, the fraction of DE-Cad molecules associated with the cytoskeleton decreases in the absence of Girdin, thereby identifying Girdin as a positive regulator of adherens junction function. Girdin mutant embryos display isolated epithelial cell cysts and rupture of the ventral midline, consistent with defects in cell-cell cohesion. In addition, loss of Girdin impairs the collective migration of epithelial cells, resulting in dorsal closure defects. It is proposed that Girdin stabilizes epithelial cell adhesion and promotes morphogenesis by regulating the linkage of the cadherin-catenin complex to the cytoskeleton.
Campbell, K. and Casanova, J. (2015). A role for E-cadherin in ensuring cohesive migration of a heterogeneous population of non-epithelial cells. Nat Commun 6: 7998. PubMed
|Loyer, N., Kolotuev, I., Pinot, M. and Le Borgne, R. (2015). DrosophilaE-cadherin is required for the maintenance of ring canals anchoring to mechanically withstand tissue growth. Proc Natl Acad Sci U S A [Epub ahead of print]. PubMed ID: 26424451
Intercellular bridges called "ring canals" (RCs) resulting from incomplete cytokinesis play an essential role in intercellular communication in somatic and germinal tissues. During Drosophila oogenesis, RCs connect the maturing oocyte to nurse cells supporting its growth. Despite numerous genetic screens aimed at identifying genes involved in RC biogenesis and maturation, how RCs anchor to the plasma membrane (PM) throughout development remains unexplained. This study reports that the clathrin adaptor protein 1 (AP-1) complex, although dispensable for the biogenesis of RCs, is required for the maintenance of the anchorage of RCs to the PM to withstand the increased membrane tension associated with the exponential tissue growth at the onset of vitellogenesis. It was shown that AP-1 regulates the localization of the intercellular adhesion molecule E-cadherin and that loss of AP-1 causes the disappearance of the E-cadherin-containing adhesive clusters surrounding the RCs. E-cadherin itself is shown to be required for the maintenance of the RCs' anchorage, a function previously unrecognized because of functional compensation by N-cadherin. Scanning block-face EM combined with transmission EM analyses reveals the presence of interdigitated, actin- and Moesin-positive, microvilli-like structures wrapping the RCs. Thus, by modulating E-cadherin trafficking, it was shown that the sustained E-cadherin-dependent adhesion organizes the microvilli meshwork and ensures the proper attachment of RCs to the PM, thereby counteracting the increasing membrane tension induced by exponential tissue growth.
|Pares, G. and Ricardo, S. (2015). FGF control of E-cadherin targeting in the Drosophila midgut impacts on primordial germ cell motility. J Cell Sci [Epub ahead of print]. PubMed ID: 26604222
Embryo formation requires tight regulation and coordination of adhesion in multiple cell types. By imaging, 3D reconstructions and genetic analysis during posterior midgut morphogenesis in Drosophila, a novel requirement was found for the conserved FGF signaling pathway in maintenance of epithelial cell adhesion, by modulation of zygotic E-cadherin. During Drosophila gastrulation, primordial germ cells (PGC) are transported with the posterior midgut while it undergoes dynamic cell shape changes. In Branchless and Breathless mutant embryos zygotic E-cadherin is not targeted to AJs causing midgut pocket collapse impacting on PGC movement. The ventral midline also requires FGF signaling to maintain cell-cell adhesion. FGF signaling regulates the distribution of zygotic E-cadherin during early embryonic development to maintain cell-cell adhesion in the posterior midgut and the ventral midline, a role that is likely crucial in other tissues undergoing active cell shape changes with higher adhesive needs.
|Jodoin, J. N., Coravos, J. S., Chanet, S., Vasquez, C. G., Tworoger, M., Kingston, E. R., Perkins, L. A., Perrimon, N. and Martin, A. C. (2015). Stable force balance between epithelial cells arises from F-Actin turnover. Dev Cell 35: 685-697. PubMed ID: 26688336
The propagation of force in epithelial tissues requires that the contractile cytoskeletal machinery be stably connected between cells through E-cadherin-containing adherens junctions. In many epithelial tissues, the cells' contractile network is positioned at a distance from the junction. However, the mechanism or mechanisms that connect the contractile networks to the adherens junctions, and thus mechanically connect neighboring cells, are poorly understood. This study identified the role for F-actin turnover in regulating the contractile cytoskeletal network's attachment to adherens junctions. Perturbing F-actin turnover via gene depletion or acute drug treatments that slow F-actin turnover destabilized the attachment between the contractile actomyosin network and adherens junctions. This work identifies a critical role for F-actin turnover in connecting actomyosin to intercellular junctions, defining a dynamic process required for the stability of force balance across intercellular contacts in tissues.
Vertebrates and invertebrates share common mechanisms for regulation of cell-cell adhesion, including a family of proteins known as cadherins. Cadherins are important in setting up boundaries between epithelial compartments, preventing cell populations with different fates from mixing with one another. They control orderly release of cells from epithelium during epithelial-mesenchymal transitions. shotgun, or DE-cadherin is a homolog of classic vertebrate cadherins. The level of shotgun, expressed from maternal mRNA throughout the entire blastoderm [Image], is high enough to sustain embryonic development except for severe disruption of Malpighian tubules (Uemura, 1996). Zygotic shg is expressed in all epithelial tissue except for presumptive mesoderm cells prior to gastrulation [Image].
The presence of shg expression in neuroectoderm, and its absence in delaminated neuroblasts, suggests an involvement of SHG in the critical process of delamination: the migration of neuroblasts from the ectoderm into the ventral nervous system (Tepass, 1996). Another cadherin, Cadherin-N shows a complementary expression pattern. It is expressed primarily in the nervous system but not in epithelial precursors of neural cells (Iwai, 1997).
E-cadherin is a cell adhesion molecule that provides one constituent of the adherens junction, a cellular junction localized at the apicolateral boundary of an epithelial cell. E-cadherin recruits other proteins to the region of cell-cell contact, such as Crumbs, a transmembrane protein involved in organizing the adherens junction, and Armadillo, a junction associated protein coded for by a pair rule gene involved in wingless signaling.
shotgun is involved in Malpighian tubule morphogenesis. Malpighian tubules are initiated by a local invagination from the hindgut primordia. In shg mutants, the Malpighian tubules are rounded and eventually disintegrate. SHG is concentrated at the apical poles of epithelial cell-cell junctions (Oda, 1994). Interestingly, the apical polarity of the cells is preserved in shg mutants as reflected in Crumbs protein distribution (Uemura, 1996).
Tracheal branch outgrowth and fusion are similarly defective in shotgun mutants. A "stall" phenotype is apparent, exhibiting delayed branch extention. armadillo mutants have similar effects on tracheal development. The role of Armadillo in tracheal morphogenesis is partly separate from that of Wingless, because the formation of dorsal tracheal trunks is only partially impaired in wg mutants. This means that the connection of wingless signaling to occurances at the apical junction is not sufficient to completely disrupt morphogenesis in wingless mutants (Uemura, 1996).
The primary role of shotgun is preservation of the integrity of Drosophila epithelium and it is downregulated during critical periods of epithelial-mesenchymal transition such as gastrulation and neurogenesis. As an epithelial cadherin, it is the central element of the adherens junction, a multiprotein complex that holds cells together and transduces adhesion signals across membranes. It is involved as the nucleation site of cytoskeleton to cell junctions. In zygotic shotgun mutants the level of alpha-catenin and Armadillo at the adherens junction is dramatically reduced, pointing to the importance of Drosophila E-cadherin in assembling the adherens junction (Tepass, 1996).
The molecular structures of classic cadherins show clear differences between chordate and nonchordate metazoans. Although nonchordate classic cadherins have cadherin superfamily-specific extracellular repeats (CRs) and a highly conserved cytoplasmic domain (CP), these cadherins have a unique extracellular domain that is absent from vertebrate and ascidian (phylum Urochordata) classic cadherins. This domain is termed here the primitive classic cadherin domain (PCCD). The PCCD consist of three motifs. The first is unique to nonchordate classic cadherins, and has been named the NC (nonchordate motif). The second is rich in cysteine residues and rather resembles EGF repeats, and has been named the CE (cysteine-rich EGF repeat-like motif). The third is similar to the laminin A globular domain, and is named the LAG (laminin A globular domain-like motif). These motifs constitute a domain that constitutes the primitive classic cadherin domain (PCCD). To understand the roles of the PCCD, a series of mutant forms of the Drosophila classic cadherin Shotgun were constructed. Biochemical analyses indicate that the last two CRs and PCCD form a special structure with proteolytic cleavage. Mutations in the PCCD do not eliminate the cell-cell-binding function of Shotgun in cultured cells, but prevent the cadherin from efficiently translocating to the plasma membrane in epithelial cells of the developing embryo. In addition, genetic rescue assays suggest that although CP-mediated control plays a central role in tracheal fusion, the role of the PCCD in efficient recruitment of Shotgun to apical areas of the plasma membranes is also important for dynamic epithelial morphogenesis. It is proposed that there is a fundamental difference in the mode of classic cadherin-mediated cell-cell adhesion between chordate and nonchordate metazoans (Oda, 1999).
When the amino acid sequences of the PCCDs of nonchordate classic cadherins are aligned, the PCCD of Shotgun shows 39.8%, 31.1%, and 27.5% amino acid sequence identity to those of Shotgun, LvG-cadherin (sea urchin), and HMR-1 (C. elegans), respectively. The PCCDs of Shotgun and Drosophila N-cadherin are the most similar to each other in all combinations. A phylogenetic tree was constructed based on the PCCDs, consistent with the tree based on the CPs. The PCCD consists of the NC, CE, and LAG. No significant similarity within the NC is found to sequences of other known proteins. The CEs have 10 or 12 conserved cysteine residues, and the LAGs have 4 conserved cysteine residues. Although sequences similar to the LAGs are found in a variety of proteins, including Drosophila Slit, Fat, Crumbs and rat neurexin I, the first two of the four cysteine residues are not conserved in proteins other than the nonchordate classic cadherins. These amino acid sequence data suggest that the PCCD forms a structure unique to nonchordate classic cadherins (Oda, 1999).
When full-length Shotgun tagged with green fluorescent protein (GFP) at the carboxyl terminus is expressed in Drosophila S2 cells, 150- and 110-kDa polypeptides named distal and proximal polypeptides (DP and PP) are detected in the cell lysates by anti-Shotgun monoclonal antibody DCAD2 and anti-GFP antibody, respectively, in addition to a small amount of the precursor (about 230 kDa). DP corresponds to the polypeptide detected in embryonic lysates by DCAD2, which recognizes the region between CR0 and CR1. A CP-deleted mutant molecule named dCPc3 is separated into a DP of the same size (150-kDa) and a PP of reduced size (80-kDa). Sequence analysis shows that protolytic removal of the signal peptide and proteolytic cleavage between G (aa 1010) and S (aa 1011) residues in the NC result in DP (aa 70-1010) and PP (aa 1011-1507). Deletion analysis indicates that the region covering CR4, CR5, NC, and CE (aa 738-1108) is necessary for NC cleavage, but this is not the case for most other regions, including the transmembrane segment (TM) (Oda, 1999).
The CR domain, PCCD, and CP are essential for the morphogenetic function of Shotgun. The morphogenetic abilities of Shotgun mutant molecules are not necessarily correlated with their adhesive abilities in S2 cells. Various extracellular-domain deletion mutants, dCR3h, dCR4h, and dEx, which have no cell-cell-binding ability, can produce positive morphogenetic effects on tracheal fusion, but dCPc3, dNc, dCL3, and inNcHA show no positive morphogenetic effects, despite having cell-cell-binding ability in S2 cells. These results indicate that CP-mediated control plays a central role in tracheal fusion. The CP binds to the catenins, which may mediate interaction with the actin cytoskeleton. This coupling is expected to translate the force of actin bundle contraction into cell shape changes. Even if cell-cell binding function is removed from Shotgun, such mechanical forces may induce incomplete tracheal fusion. Despite the intact CP, some mutations in the PCCD lead to complete loss of the morphogenetic ability of Shotgun. These mutant molecules fail in prompt translocation to the plasma membrane when expressed in epithelial cells of the developing embryo. Efficient recruitment of Shotgun to appropriate sites of the plasma membrane may be important for dynamic epithelial morphogenesis during development (Oda, 1999).
Shotgun protein must be translocated from the ER to the contact sites of the plasma membrane to participate in cell-cell binding. Exogenously expressed normal Shotgun immediately accumulates at apicolateral borders of the plasma membrane in tracheal cells and many other epithelial cells. Mutational analyses reveal important aspects of Shotgun translocation involving the last two CRs, PCCD, and CP. Mutations in the PCCD lead to strong accumulation of the molecules in subdomains of the cytoplasm probably corresponding to the ER. Deletion of the large extracellular region encompassing CRs 1-5 and the PCCD also reduce the efficiency of translocation. These observations favor the idea that the extracellular region, including the PCCD, has an active role in translocation out of the ER to the plasma membrane. Deficiencies in deletion mutants dCR3h or dCR4h have little effect on translocation, but dCR4 exhibits a defect similar to that of the PCCD mutant molecules. These observations suggested that the last two CRs are functionally linked with the PCCD, and that this set is required for normal translocation. It is intriguing that NC cleavage, which presumably takes place in the ER, also requires the same region. However, the results from mNcGSP and dCL3 indicate that NC cleavage is not a prerequisite for translocation and occurs even under conditions in which translocation is blocked. It is speculated that CRs 4 and 5 and the PCCD are an overlapping region required for NC cleavage and for translocation, but these two events occur independently. There are three possible explanations for the mechanism of the involvement of the PCCD in translocation. (1) The unique structure of the last two CRs and PCCD may interact in the ER lumen with some machinery that carries out protein sorting and directional transport. (2) The PCCD structure may be involved in a lateral interaction (between the synthesized cadherin proteins) that facilitates translocation. (3) The PCCD may have a role in folding the extracellular part of the synthesized cadherin in the ER lumen to form the compact structure necessary for efficient translocation. It is hypothesized that the common ancestor of chordate classic cadherins adopted an alternative translocation mechanism to the PCCD-mediated mechanism coincident with the structural change to small size (Oda, 1999).
The CP is another part essential for normal translocation of Shotgun. Although the CP-deleted molecule tends to translocate to the apical plasma membrane, it is not so actively concentrated into the sites of cell-cell contact. Despite the reduced efficiency of translocation, the mutant molecule lacking the large extracellular region appears to be recruited to the apical zones of cell-cell contact once it leaves the ER. It seems that the CP-mediated control plays an important role in efficient and directional translocation of Shotgun from the ER to the contact sites of the plasma membrane. Shotgun mutant molecules accumulating in the cytoplasm due to the lack of translocation appear to bind to Armadillo and alpha-catenin. This raises the possibility that normal Shotgun joins Armadillo and alpha-catenin before arriving at the plasma membrane (Oda, 1999).
In addition to the subcellular distributions of the classic cadherins, there are marked differences between chordates and nonchordates in junctional complexes. Adherens junctions (AJs) and septate junctions (SJs) are observed in a wide range of nonchordate metazoans by electron microscopy. The AJ is located at the apical-most portion of the cell, followed by the SJ. In chordates (including vertebrates and ascidians) tight junctions (TJs), in addition to AJs, are frequently found, but SJs have not been found. Exceptionally, in Amphioxus cephalochordata, neither TJs nor SJs have been observed. The TJ is positioned at the apical end of the lateral plasma membrane in chordate epithelial cells, followed by the AJ. These observations indicate that there are fundamental differences between chordate and nonchordate metazoans not only in cadherin-based cell-cell adhesion but also in other mechanisms of cell-cell connection (Oda, 1999).
Cytokinesis entails cell invagination by a contractile actomyosin ring. In epithelia, E-cadherin-mediated adhesion connects the cortices of contacting cells; thus, it is unclear how invagination occurs, how the new junction forms, and how tissue integrity is preserved. Investigations in Drosophila embryos first show that apicobasal cleavage is polarized: invagination is faster from the basal than from the apical side. Ring contraction but not its polarized constriction is controlled by septin filaments and Anillin. Polarized cleavage is due instead to mechanical anchorage of the ring to E-cadherin complexes. Formation of the new junction requires local adhesion disengagement in the cleavage furrow, followed by new E-cadherin complex formation at the new interface. E-cadherin disengagement depends on the tension exerted by the cytokinetic ring and by neighboring cells. This study uncovers intrinsic and extrinsic forces necessary for cytokinesis and presents a framework for understanding how tissue cohesion is preserved during epithelial division (Guillot, 2013).
Epithelial cells divide in the plane of the tissue, allowing the equal partitioning of polarity proteins. This study delineated two major events during epithelial cytokinesis that shed light on how this is controlled. Cleavage progresses along the apicobasal axis and is polarized, as it is faster from basal to apical. This is not due to polarized contraction of the ring but to apical anchoring of the ring to E-cad complexes. Second, cleavage occurs in the plane of junction and involves local adhesion disengagement. In contrast to standard cytokinesis, this study delineated intrinsic and extrinsic mechanical processes operating during epithelial cytokinesis. Contractility of the ring itself is dependent on septins and Anillin. Ring contraction is resisted by intercellular adhesion mediated by E-cadherin complexes and by tension from neighboring cells transmitted by adhesion. Thus, E-cad-based adhesion plays a pivotal role in epithelial cytokinesis by anchoring the contractile ring, while its disengagement uncouples intrinsic and extrinsic tensile activity (Guillot, 2013).
In Drosophila embryos, epithelial cells exhibit polarized cleavage furrow ingression. This is likely to be general in epithelial cells, albeit at different magnitudes. MDCK cells too divide from the basal side toward the apex, and neuroepithelial cells in vertebrates partition the basal body first before the more apical part of the cell. Polarized cleavage is not a property unique to epithelial cells, however. Embryonic cleavage in several species exhibit a range of patterns, from completely unilateral cleavage, as reported in jellyfish (Clytia and Beroe) and Ctenophores (Pleurobrachia), to partly asymmetric cleavage in the one-cell-stage C. elegans embryos). In the latter case, polarized ingression of the cleavage furrow is stochastic and correlates with heterogeneities in the recruitment of the actin crosslinker Anillin and of septins. In anillin and septin knockdowns, cleavage becomes symmetric. This contrasts with activators of MyoII, such as Rho kinase, which affects the speed of contraction but not its polarity. Thus, in nonepithelial cells, polarized cleavage is a purely autonomous process governed by heterogeneities in regulators of contractility. This study found, however, that in Drosophila embryos, polarized cleavage is not determined by polarized distribution of Anillin and septins or by differential biomechanical properties of the ring. Septins display a marginal yet significant enrichment basally, and Anillin is slightly enriched apically. However, invagination was still normally polarized along the apicobasal axis in both peanut mutants and anillin RNAi embryos, despite strong reduction in constriction rat. Moreover, no significant difference between apical and basal relaxation kinetics was detected following ablation in wild-types. The ablation kinetics reflects the relative effect of stiffness in the ring and friction internal to the ring and with the cytoplasm. With the caveat that the latter cannot be directly measured and and is assumed to be uniform, these ablation experiments indicate the relative stiffness in the ring. The fact that relaxation is faster (<5 s) than turnover of the internal components of the ring, such as MyoII, substantiates the idea that mostly the elastic relaxation of the ring was measured and not a quasi-static relaxation associated with turnover/movements of ring components (Guillot, 2013).
The rate of constriction was monotonic such that big rings and small rings contracted at a constant rate in wild-types but also in anillin or septin mutants, although it was strongly reduced in the latter cases. This contrasts with reports in C. elegans, where constriction was scaling with ring size, suggesting a mechanism based on disassembly of contractile units whose number scales with ring size. This difference may stem from the fact that cytokinesis is especially rapid in Drosophila embryos (about 150 s). Alternatively, it could reflect the epithelial nature of the divisions reported in this study (Guillot, 2013).
The evidence argues instead that polarized ingression depends largely on apical anchoring of the ring to E-cad complexes. First, E-cad complexes colocalize with the contractile ring for the most part of invagination. Second, ingression is symmetric in either e-cad or α-cat RNAi embryos. Although E-cad complexes, in particular α-cat, can recruit regulators of MyoII, this cannot explain polarized invagination of the ring, since apical and basal relaxations are not significantly different in wild-types and in α-cat RNAi embryos. E-cad complexes transmit actomyosin tension in epithelia. Two sets of observation support the idea that junctions exert pulling forces on the ring due to anchoring. The ring is stretched laterally as it constricts, and this requires apical junctions via e-cad and α-cat. The relative deformation of the ring following ablation is larger apically than basally, and this also requires cell junctions. It is striking that extrinsic and intrinsic regulators of the ring contraction have very different effects on ring dynamics. In the absence of Pnut or Anillin, the ring constriction is reduced but it is still polarized. However, following e-cad or α-cat depletion, ring constriction is normal but symmetric. It is concluded that the mechanical connection of E-cad complexes to the contractile ring causes polarized invagination. It is possible that, in other systems, both intrinsic and extrinsic regulation will operate in parallel to increase the cleavage asymmetry. This may be important in highly columnar epithelial cells or when adhesion is lower and unable to resist the ring tension (Guillot, 2013).
Polarized cleavage effectively separates apical and basal cleavage, adhesion complexes being a barrier separating the apical and lateral domains. The central problem becomes: How does cleavage occur at adherens junctions? This study delineated two critical phases in junctional cleavage. First, the adherens junctions invaginate with the actomyosin ring, consistent with the fact that the ring is anchored to the junctions. During this phase, E-cad intercellular adhesion is stable in the face of the tension exerted by the ring, and E-cad colocalizes with the ring at the point of coupling. Invagination of junctions then stops as E-cad levels decrease in this area. However, ring constriction continues and appears to detach from junctions. This is interpreted as a point of adhesion disengagement. Adhesion disengagement marks the formation of the new vertices and of the new junction between daughter cells. Electron microscopy images show this membrane disengagement. Consistent with this, the membrane still invaginates with the actomyosin ring), although E-cad is still not detected. Closer examination shows that E-cad monomers are present at this late stage of cytokinesis but that adhesion complexes form gradually from this stage onward. It is striking that adhesion is very locally (<1 μm out of ∼40 μm of junction perimeter) and transiently (∼200 s) perturbed during division. In the first 150 s, E-cad clusters immediately adjacent to the cleavage furrow remain in position as the junction invaginates. This suggests that the cortex can be extensively remodeled locally. It likely reflects the fact that tension induces membrane flows with respect to the actin-rich cortex and argues that E-cad-mediated adhesion does not prevent membrane flow during disengagement. Interestingly, local disengagement allows local cell deformation without affecting the overall shape of cell contacts. Consistent with the idea that adhesion is locally disengaged, the amount of E-cad has a strong impact on the timing and depth of junctional cleavage. Increasing E-cad delays disengagement (i.e., the formation of the new junction, inducing strong cell deformations. More generally, this implies that increasing adhesion may provide an efficient mechanism to prevent local cell-cell disengagement when internal tension is used to remodel junctions during morphogenesis. In apical constriction in the Drosophila mesoderm, actomyosin cables pull on the junctional cortex and reduce junction lengths. If adhesion was not strong enough, local disengagement would occur and junctions could not remodel. The fact that adhesion disengagement is local and transient during cytokinesis is also probably key to the overall maintenance of cell polarity and adhesion during epithelial division (Guillot, 2013).
It is proposed that adhesion disengagement is mechanically induced by tension in the cytokinetic ring and by tension from neighboring cells. When the cumulated tension is higher that the adhesive force, disengagement occurs. Consistent with this, disengagement and formation of the new junction is strongly delayed in mutants that reduce the constriction of the cytokinetic ring, namely, in septin mutants and in Anillin knockdown embryos. Likewise, ablation of neighboring cells delays disengagement. It is, however, possible that adhesion is also locally disrupted by either E-cad endocytosis or phosphorylation of β-cat/Arm (Guillot, 2013).
Adhesion complexes transmit cell tension exerted by neighboring cells. Surrounding junctions and, more specifically, MyoII cables oriented toward or near the cleavage furrow strongly affect furrow invagination when E-cad is present at high levels. The invagination in this case is very shallow, suggesting a tug of war between intrinsic (ring contraction) and extrinsic tension (MyoII cables in neighbors). This results in asymmetric furrows in the plane of junctions due to the asymmetric distribution of MyoII cables around the cell. When E-cad is expressed at lower levels, even if surrounding junctions are oriented toward the cleavage furrow, invagination is unaffected and symmetric. It is proposed that E-cad complexes sensitize cells to their mechanical environment. This may provide a mechanism for cells to integrate stress coming from the environment. It will be important to explore how E-cad levels may affect cells responsiveness to extrinsic stress during division by affecting the timing of the formation of the new junction by local disengagement and the resulting cell shape and topology (Guillot, 2013).
The Drosophila homolog of classic vertebrate cadherins is DE-cadherin. The extracellular domain of DE-cadherin has six cadherin-specific repeats, although the first repeat seems to be cleaved off upon maturation, and the cytoplasmic domain shows significant identity to that of classic vertebrate cadherins. DE-cadherin is distinguishable from its vertebrate counterparts by a large insertion between the last cadherin repeat and the transmembrane domain, with local sequence similarity to Fat, Laminin A chain, Slit, and Neurexin I at the proximal region of the extracellular domain. This domain has two motifs, one a cysteine rich domain similar to Fat EGF repeat 3. The other is a laminin A globular-domain (G-domain) repeat (Oda, 1994).
The enormous size of Cadherin-N is primarily due to the presence of 15 cadherin repeats in the extracellular region, presenting a contrast to the 4 repeats in all vertebrate classic cadherins and the 6 repeats in Shotgun, the Drosophila E-cadherin. Both Drosophila cadherins have insertions of similar sequences between the last extracellular cadherin repeat and the membrane-spanning segment. The insert contains a series of subdomains: an Fcc box (fly classic cadherin box), a cysteine-rich segment (C-rich 1), a laminin A (See Drosophila Laminin A) globular segment (LmA-G), and another cysteine-rich segment (C-rich 2). The Fcc box, comprising 170 amino acids is defined as such because database searches with its sequences identify only the comparable regions of Shotgun as a relative. Similar sequences are not found in vertebrate cadherins. The whole Cadherin-N LmA-G displays 25% sequence identity to mouse laminin A and to the presynaptic transmembrane protein Neurexin. The Cadherin-N cytoplasmic domain is much more similar to those domains of Shotgun and vertebrate classic cadherins with respect to both size and sequence. The intracellular domains of the two Drosophila cadherins and mouse N-cadherin range between 157 and 160 amino acids in length, and have 37% and 46% sequence identity in any combination among them, with the higher figure representing the Cadherin-N identity to murine N-cadherin, and the lower representing Shotgun identity to murine N-cadherin. The degree of sequence conservation between the two Drosophila cadherins (41% identity) is lower than the 63% identity between N- and E-cadherin in the same vertebrate species, as for example, in mice (Iwai, 1997).
date revised: 20 APR 97
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