Surprisingly, there is a difference in the distributions of Talin mRNA and protein during embryogenesis. In particular, high levels of mRNA in the nerve cord do not correspond to high protein levels. Early homogeneous staining for Talin mRNA is followed by prominent expression in the ventral nerve cord. Talin is expressed in a subset of ventral cord neurons (Brody, 2000 and 2002). Lower levels of mRNA are more broadly distributed, with enrichment in the gut and muscle attachment sites detected at stage 16. That this pattern is specific for this transcription unit was shown by testing with probes from four different parts of the transcript, including the C-terminal region to which antibodies were raised; deletion of the Talin gene (rhea79a) eliminates staining (Brown, 2002).
To examine the distribution of Talin protein, polyclonal and monoclonal antibodies were made against the C terminus of Talin. Five of the monoclonal antibodies recognize different epitopes on Drosophila Talin. All but one of the anti-Talin antibodies produced indistinguishable patterns of staining on fixed embryos. The one exception is a monoclonal antibody, J18, that crossreacts with an antigen expressed in three cells per hemisegment within the central nervous system (Brown, 2002).
Analysis of Talin protein distribution during embryogenesis shows that it is maternally deposited and is evenly distributed in the cytoplasm following cellularization. Talin becomes progressively concentrated at the membrane, first detected in the migrating primordial midgut cells and then at muscle attachment sites, where the muscles and epidermal cells are linked via integrins. Talin protein shows only a hint of the strong pattern of mRNA expressed in the nervous system. Consistent with the low level of protein in the nervous system, zygotic mutant rhea embryos do not have any defects in the structure of the nervous system, as assayed with glial and neuronal cell markers. The subcellular distribution of Talin at the muscle attachment sites was examined by immunoelectron microscopy (IEM). Talin is found within submembranous electron-dense material associated with the hemiadherens junctions at muscle attachment sites (Brown, 2002).
Most sites of Talin concentration at membranes correspond to sites of integrin concentration, and colocalization of the two proteins is seen at the edge of the epidermis, during dorsal closure, and at muscle attachments. No PS integrin staining lacking colocalized Talin was observed. However, Talin is concentrated at the membrane of some cells lacking integrin. This is clearest in the gonadal mesoderm, where recruitment of Talin to the cortex of the gonadal mesoderm cells occurs as the gonad condenses. To test whether recruitment of Talin to sites of integrin expression requires integrins, Talin distribution was examined in embryos lacking PS integrins. Embryos lacking the ßPS subunit show a loss of Talin concentration at muscle attachment sites. In embryos that lack the mesodermally expressed alphaPS2 integrin subunit, but that still contain epidermal PS1 (alphaPS1ßPS) integrin, Talin is lost from muscle ends but still concentrated at the basal ends of the attaching epidermal cells, the tendon cells. These results show that Talin is recruited from the cytoplasm by integrins in both cell layers of the muscle attachment site (Brown, 2002).
The absence of strong ßPS expression in the gonadal mesoderm suggests that a receptor different from and other than integrin recruits Talin to the membrane in this tissue. Consistent with this, removal of ßPS from the embryo does not alter Talin enrichment in the gonadal mesoderm, nor does removal of the other Drosophila ß integrin subunit, ßnu. This shows that recruitment of Talin in the gonadal mesoderm is not driven by integrins. An alternative candidate would be Layilin (Borowsky, 1998), but no clear ortholog of this protein is encoded in the Drosophila genome (Brown, 2002).
Organogenesis of the somatic musculature in Drosophila is directed by the precise adhesion between migrating myotubes and their corresponding ectodermally derived tendon cells. Whereas the PS integrins mediate the adhesion between these two cell types, their extracellular matrix (ECM) ligands have been only partially characterized. This study shows that the ECM protein Thrombospondin (Tsp), produced by tendon cells, is essential for the formation of the integrin-mediated myotendinous junction. Tsp expression is induced by the tendon-specific transcription factor Stripe, and accumulates at the myotendinous junction following the association between the muscle and the tendon cell. In tsp mutant embryos, migrating somatic muscles fail to attach to tendon cells and often form hemiadherens junctions with their neighboring muscle cells, resulting in nonfunctional somatic musculature. Talin accumulation at the cytoplasmic faces of the muscles and tendons is greatly reduced, implicating Tsp as a potential integrin ligand. Consistently, purified Tsp C-terminal domain polypeptide mediates spreading of PS2 integrin-expressing S2 cells in a KGD- and PS2-integrin-dependent manner. A model is proposed in which the myotendinous junction is formed by the specific association of Tsp with multiple muscle-specific PS2 integrin receptors and a subsequent consolidation of the junction by enhanced tendon-specific production of Tsp secreted into the junctional space (Subramanian, 2007).
The abnormal pattern of the somatic muscles in the tsp mutant embryo raised the possibility that the muscle-tendon integrin-mediated adhesion is defective in the mutant embryos. A hallmark of appropriate integrin-mediated adhesion is the accumulation of Talin at the cytoplasmic face of the hemiadherens junction, where it binds directly to the integrin cytoplasmic domain, modulating its ligand affinity and recruiting actin microfilaments to this site. A significant reduction of accumulated Talin levels in tsp mutant embryos is observed. Whereas Talin is still detected at the sites of muscle-muscle junctions, it was entirely missing at sites where individual muscles would normally form junctions with single tendon cells, in particular at the junction sites formed between the lateral transverse muscles and their corresponding tendon cells. The lack of Talin at these sites corresponds with the lack of ßPS-integrin staining and is consistent with the loss of appropriate myotendinous junction. Thus, in the absence of functional Tsp, individual myotubes fail to form integrin-mediated adherens junction with tendon cells (Subramanian, 2007).
The genetic locus that encodes Talin is rhea. The first two alleles, rhea1 and rhea2, were isolated in the wing blister screen (Prout, 1997). Two other alleles, rhea17 and rhea3, were isolated as mutations that dominantly enhance weak integrin mutations. The rhea1 and rhea2 alleles were mapped to 66D5-6. By locally hopping a P element in this region, which is not allelic to rhea, l(3)S1760, rhea79a was generated. The P element in this strain is inserted in the same position as l(3)S1760, within the coding region of the Drosophila ortholog of ergic-53, but is deleted for the ergic-53 coding region, leading to the initial suggestion that rhea encodes ergic-53. However, recombinational analysis placed rhea1 0.08 map units (25-50 kb) from the l(3)S1760 P element. The gene adjacent to ergic-53 was revealed to be Talin by the genome sequence. It was then found that Talin protein is reduced in rhea mutant embryos and imaginal disc clones and that Talin mRNA is absent in rhea79a (Brown, 2002).
To confirm that rhea is the Talin gene, the Talin-coding region was sequenced from rhea1 and rhea2. For each allele a small deletion was found that produces a frameshift in the Talin-coding sequence. For rhea1 the frameshift occurs after amino acid 1139, and the new reading frame terminates after two amino acids in the wrong frame. For rhea2 the frameshift occurs after amino acid 1279 and terminates after 31 out of frame amino acids. Inverse PCR was used to identify the proximal insertion site of the P element in rhea79a, which was found to be 1931 bp downstream of Talin, showing that the rhea79a deficiency deletes three genes, ergic-53, Talin, and CG6638. Each rhea allele has an aberration in the Talin coding sequence. A mutant deficient for Ergic53 complements rhea1, rhea2, and rhea17. Therefore, it is concluded that rhea encodes Talin (Brown, 2002).
Three aspects of the Talin mutant phenotype have been described (Prout, 1997). Clones of rhea/rhea cells in the wing do not attach to the other cell layer of the wing, causing a wing blister. The two initial alleles and two recently identified ones (rhea3 and rhea17) dominantly enhanced the wing blister phenotype of hypomorphic alleles of integrin genes (Prout, 1997). Finally, rhea mutant embryos have a detachment of the epidermis from the muscles, although the muscles remain attached end to end. The embryonic phenotype of Talin mutants was examined by EM, with particular attention to tendon cells. In wild-type embryos, tendon cells are spanned by microtubules that link basal hemiadherens junctions to tonofibrils that insert into the apical exoskeleton, thereby transferring the force of muscle contraction to the exoskeleton. In rhea/rhea cells, microtubules extended from apical tonofibrils toward the basal membrane, but mature basal attachment sites fail to form. Structural features of normal attachment sites, such as extensive folding of basal membranes and linkage of microtubules to the inner surface of basal membranes, are not generally present in rhea tendon cells. Also, in these rhea mutant tendon cells, microtubules are abnormally oriented, in some cases running parallel, rather than perpendicular, to the exoskeleton. Loss of Talin results in reduction of electron-dense material from the cytoplasmic face of hemiadherens junctions at muscle attachment sites. This suggests that Talin and/or the proteins it recruits make a significant contribution to this dense material (Brown, 2002).
These zygotic rhea mutant embryos still have some maternally deposited Talin. To analyze the phenotype resulting from the complete absence of Talin, the maternal contribution was removed by generating germline clones. Half of these rhea/rhea eggs receive a wild-type paternal allele, and the zygotic expression of Talin rescues the absence of maternal Talin in some, but not all, embryos. The number of hatching embryos varied from 33%–41%, rather than the expected 50% (depending on the allelic combination). Viable fertile adults developed from hatched embryos. Thus, maternal deposition of Talin protein is important, but not essential, for normal development (Brown, 2002).
Embryos lacking both maternal and zygotic talin have a stronger phenotype than those lacking either maternal or zygotic product, the most prominent features of which are a failure in germband retraction and strong muscle detachment. This phenotype is very similar to that of embryos lacking both maternal and zygotic ßPS. The similarities between the two phenotypes suggest that talin is essential for integrin function. Close examination of the muscle phenotype provides insight into the role of Talin in integrin-mediated adhesion. PS2 (alphaPS2ßPS) integrin localizes normally, demonstrating that integrins reach the cell surface and localize to the ends of muscles in the absence of talin. In detached muscles, actin staining is separate from PS2 integrin staining. This demonstrates that integrin is able to bind to the ECM, since, if it could not, it would be expected to remain on the surface of the detached muscle. Thus, a separation is seen between integrins and actin, not between integrins and the ECM, suggesting that the primary role of talin is to link integrins to the cytoskeleton, and not to stimulate their ligand binding. Talin does not appear to be required for condensation of the gonad, since this occurs in some mutant embryos. Condensation does fail in some embryos, but this could be a secondary effect caused by other morphogenetic defects. By examining different rhea alleles, it has been confirmed that this represents the null Talin phenotype. The phenotypes of mutant embryos from germline clones of rhea1 and rhea2 are indistinguishable, as are those of rhea79a, which deletes rhea and two flanking genes. Other data suggest, however, that the rhea1 and rhea2 mutations are weak dominant negatives. For example, producing rhea2/rhea79A embryos from maternal germline clones of rhea2 causes 65% (n = 153) failure of germ band retraction, while those of the rhea79A deficiency caused only 48% failure (Brown, 2002).
Further insight into the role of Talin was gained by looking at Talin and integrins in the imaginal disc epithelia. Just prior to pupariation it has been found that Talin and integrins colocalize into focal adhesion-like structures at the basal surface of the wing imaginal disc. Making clones of cells mutant for rhea results in loss of the staining of these structures with the Talin antibody. The clusters of Talin also fail to form in clones of cells lacking the ßPS integrin subunit. Clustering of integrins into these focal adhesion-like structures requires Talin function, as it does not occur in clones of cells lacking Talin. Therefore, clustering of integrins requires Talin, and clustering of Talin requires integrins. Loss of Talin does not grossly impair the rate of proliferation of the imaginal disc cells, since mutant clones are of a similar size to the wild-type twin spots. In addition, loss of Talin does not alter overall levels of integrin synthesis. Combining these results with those from the embryo suggests that Talin's role may be to promote integrin clustering, which, in turn, allows the establishment of a strong connection with the cytoskeleton (Brown, 2002).
The involvement of Talin in the transmission of integrin signals regulating gene expression was also examined. In Drosophila one signaling assay uses the enhancer trap 258, which is expressed in the midgut and fails to be repressed in the absence of PS1 integrin. The expression of this integrin target gene was examined in the absence of Talin. In embryos lacking maternal and zygotic Talin, midgut development was too disrupted to assay 258 expression. In the absence of the zygotic Talin, the midgut shows the characteristic phenotype of an integrin mutation: the gastric caeca fail to split from two initial evaginations into four slender tubes, the midgut does not elongate into a slender tube, and the proventriculus does not form properly. Despite these morphological defects, the 258 gene was repressed. The same result was obtained in more than 30 mutant midguts. While the possiblility cannot be ruled out that the small amount of maternal Talin left is sufficient for integrin signaling, but not for integrin adhesion, these results suggest that Talin is not required for integrin signaling to the nucleus (Brown, 2002).
Integrins are evolutionarily conserved transmembrane alpha,beta heterodimeric receptors involved in cell-to-matrix and cell-to-cell adhesions. In Drosophila the position-specific (PS) integrins mediate the formation and maintenance of junctions between muscle and epidermis and between the two epidermal wing surfaces. Besides integrins, other proteins are implicated in integrin-dependent adhesion. In Drosophila, somatic clones of mutations in PS integrin genes disrupt adhesion between wing surfaces to produce wing blisters. To identify other genes whose products function in adhesion between wing surfaces, a screen was conducted for autosomal mutations that produce blisters in somatic wing clones. Seventy-six independent mutations in 25 complementation groups were isolated, 15 of which contain more than one allele. Chromosomal sites were determined by deficiency mapping, and genetic interactions with mutations in the beta PS integrin gene myospheroid were investigated. Mutations in four known genes (blistered, Delta, dumpy and mastermind) were isolated. Mutations were isolated in three new genes (piopio, rhea and steamer duck) that affect myo-epidermal junctions or muscle function in embryos. Mutations in three other genes (kakapo, kiwi and moa) may also affect cell adhesion or muscle function at hatching. These new mutants provide valuable material for the study of integrin-dependent cell-to-cell adhesion (Prout, 1997).
Epithelial tubes that compose many organs are typically long lasting, except under specific developmental and physiological conditions when network remodeling occurs. Although there has been progress elucidating mechanisms of tube formation, little is known of the mechanisms that maintain tubes and destabilize them during network remodeling. This study describes Drosophila tendrils mutations that compromise maintenance of tracheal terminal branches, fine gauge tubes formed by tracheal terminal cells that ramify on and adhere tightly to tissues in order to supply them with oxygen. Homozygous tendrils terminal cell clones have fewer terminal branches than normal but individual branches contain multiple convoluted lumens. The phenotype arises late in development: terminal branches bud and form lumens normally early in development, but during larval life lumens become convoluted and mature branches degenerate. Their lumens, however, are retained in the remaining branches, resulting in the distinctive multi-lumen phenotype. Mapping and molecular studies demonstrate that tendrils is allelic to rhea, which encodes Drosophila talin, a large cytoskeletal protein that links integrins to the cytoskeleton. Terminal cells mutant for myospheroid, the major Drosophila ß-integrin, or doubly mutant for multiple edematous wings and inflated α-integrins, also show the tendrils phenotype, and localization of myospheroid ß-integrin protein is disrupted in tendrils mutant terminal cells. The results provide evidence that integrin-talin adhesion complexes are necessary to maintain tracheal terminal branches and luminal organization. Similar complexes may stabilize other tubular networks and may be targeted for inactivation during network remodeling events (Levi, 2006; full text of article).
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date revised: 25 August 2007
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