Drosophila Myd88 is expressed in embryos, larvae and adults. Expression is not increased during embryonic development and metamorphosis. Myd88 is also expressed in the macrophage-like cell lines S2 and l(2)mbn, that are responsive to LPS and the cytokine-like polypeptide Spaetzle. Expression of Myd88 mRNA was not noticeably upregulated by bacterial challenge in larvae or adults or by LPS treatment of cell lines (Tauszig-Delamasure, 2002).
Transgenic fly lines were established in which the Myd88 cDNA was placed under the control of a multimer of the yeast UASGal4 motif. Female flies containing both the UAS-Myd88 transgene and the fat body-specific ylk-Gal4 driver constitutively express Drosomycin (Drs) in amounts similar to those seen after septic injury in wild-type flies. Constitutive expression of Mtk (encoding another antifungal peptide, Metchnikowin) is also seen in these flies. In contrast, the antibacterial peptides are not induced by Myd88 overexpression in transgenic flies (Tauszig-Delamasure, 2002).
Epistasis experiments further show that overexpression of Myd88 does not induce Drs expression in flies carrying loss-of-function mutations in the genes encoding Tube or Pelle, demonstrating that Myd88 is a component of the Toll pathway and indicating that it probably acts upstream of Tube and Pelle in the Toll receptor complex (Tauszig-Delamasure, 2002).
To address a possible role of Myd88 later in embryogenesis, its pattern of expression was determined by in situ hybridization. During germ band retraction, strong expression is observed in the migrating anterior and posterior midgut primordia. At stage 14, endoderm expression resolves into four bands along the gut and Myd88 expression is also detected in the salivary glands and in the anal plate. Later on, at stage 16, weak expression is observed in the most anterior portion of the midgut and in the first and third midgut constrictions. Thus Myd88 is not detected in the domains where Toll has been shown to have a zygotic function, namely the epidermis and the somatic musculature, suggesting that Toll might function independently of Myd88 (Kambris, 2003).
In Drosophila, the dorsoventral axis is set up by the action of the dorsal group of genes and cactus, all of which have been ordered genetically in a linear pathway. krapfen (kra) has been identified as a new member of the dorsal-group genes. kra encodes for the Drosophila homolog of MyD88, an adapter protein operating in the mammalian IL-1 pathway. Epistasis experiments reveal that Myd88/krapfen acts between the receptor Toll and the cytoplasmic factor Tube. There is a direct interaction between Krapfen and Tube presumably mediated by the death domains present in both proteins. Tube in turn interacts with its downstream effector Pelle through death domain association. It is therefore suggested that upon Toll activation, Krapfen associates with Pelle and Tube, in an heterotrimeric complex (Charatsi, 2003).
Originally, the krapfen (kra) mutation kra56 was identified in a genetic screen for new maternal genes involved in embryonic pattern formation. The embryos laid by homozygous kra56 females fail to gastrulate properly and die as hollow tubes of dorsal cuticle. This phenotype is undistinguishable from those caused by mutations in the dorsal group of genes. However, kra56 did not fall into any known complementation group. In order to investigate the role of kra in the dorsal pathway, the presence of the mesoderm, which is formed by the ventral most cells, was tested for. The expression of the mesodermal marker Twist was examined in early blastoderm embryos. In contrast to the wild type situation where upon Toll activation Twist is expressed ventrally, in kra mutant embryos, as in other dorsal group gene mutants, Twist is absent. These results show that Myd88 is a new member of the dorsal group of genes (Charatsi, 2003).
Whether Kra participates in the activation of the Toll receptor or cooperates in the signal transduction downstream of Toll was investigated. The effect of loss of maternal kra was tested in a dominant Toll background, Toll9Q, which is a ligand-independent gain-of-function allele of Toll. Embryos laid by Toll9Q heterozygous flies show a strongly ventralized phenotype due to the constitutively active Toll that signals throughout the embryo circumference. Embryos laid by females with the genotype kra1/kra1; Toll9Q/TM3 show a complete dorsalized phenotype. Thus, kra suppresses the constitutive Toll signal, indicating that Kra acts downstream of the Toll receptor. This finding suggests that Kra operates in the cytoplasmic compartment of the Drosophila early embryo. In order to place Kra upstream or downstream of the cytoplasmic protein Tube, the phenotype of kra embryos was analzyed after microinjection of the gain-of-function construct of Tube, pBtor4021Tube. In this construct, the intracellular kinase domain of a gain-of-function allele of the receptor tyrosine kinase torso is replaced by the tube coding sequence. pBtor4021 fusions show that Tube operates upstream of Pelle. Whereas uninjected kra embryos develop only dorsal epidermis, kra embryos injected with pBtor4021Tube RNA can specify ventrolateral fates and restore ventrolateral pattern elements, such as ventral denticle belts and Filzkörper, that are never observed in kra mutant embryos. Through these methods kra can be placed downstream of Toll and upstream of tube (Charatsi, 2003).
The genetic positioning of kra between Toll and tube, however, is not informative as to the physical interactions that take place during signal transduction. In order to investigate the molecular role of kra, a yeast two hybrid assay was performed. In the yeast two hybrid assay, wild type Kra as well as Kra56, which is an EMS allele carrying a missense mutation within the TIR domain, were both able to interact strongly with Tube. This indicates that the TIR domain is not required for a Kra-Tube interaction (Charatsi, 2003).
Pelle interacts with Tube through death domain association. In the same yeast two hybrid experiment, no direct interaction was found between Pelle and Kra. This suggests that Tube could mediate the formation of a complex by association with both Pelle and Kra (Charatsi, 2003).
The epistasis experiment placed Kra downstream of the receptor Toll. Both Toll and Kra contain TIR domains, which could potentially mediate their interaction. Additionally, the kra56 allele, which shows a dorsalized phenotype presumably caused by a defective TIR domain, strongly suggests that this cytoplasmic domain plays an essential role in signal transduction. An interaction between Kra and Toll, which is not necessarily direct, is supported by immunoprecipitation experiments in which Kra/Myd88 coimmunoprecipitates with Toll. However, in the yeast two hybrid assay, no direct interaction was found between the TIR cytoplasmic domain of Toll and Kra (Charatsi, 2003).
In order to understand how the signal is transduced to Kra through Toll, the possibility that Kra homodimerizes was investigated. In mice, MyD88 is known to form homodimers in vivo through death domain-death domain and TIR-TIR interactions. Kra does not homodimerize in the yeast two hybrid assay nor in immunoprecipitation experiments (Charatsi, 2003).
Overexpression of Myd88 is sufficient to induce expression of the antifungal peptide Drosomycin, and induction of Drosomycin is markedly reduced in Myd88-mutant flies. Myd88 interacts with Toll through its TIR domain and requires the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. Myd88-mutant flies are highly susceptible to infection by fungi and Gram-positive bacteria, but resist Gram-negative bacterial infection much as do wild-type flies. Phenotypic comparison of Myd88-mutant flies and Myd88-deficient mice show essential differences in the control of Gram-negative infection in insects and mammals (Tauszig-Delamasure, 2002).
The innate immune system is centrally involved in the recognition and control of the early stages of infection in all animals. This response depends on nonclonally distributed receptors -- called pattern recognition receptors (PRRs) -- that are activated by pathogen-associated molecular patterns (PAMPs), which are conserved in microbes but absent from host tissues. PAMPs include lipopolysaccharides (LPS) in Gram-negative bacteria, peptidoglycan (PGN) and lipoteichoic acid (LTA) in Gram-positive bacteria, unmethylated CpG motifs in bacterial DNA, and flagellin. In gnathostome vertebrates, the immune system contains a second arm -- an adaptive immune system that is based on the clonal expansion of T and B lymphocytes expressing specific antigen receptors. Accumulating evidence indicates that signals generated by the innate immune system are necessary to prime adaptive immunity (Tauszig-Delamasure, 2002).
In Drosophila, immune-induced activation of Toll depends on the activation of a proteolytic cascade in the hemolymph or in the extracellular matrix surrounding the fat body. The cascade culminates in the cleavage of the secreted cytokine-like polypeptide Spaetzle and the activation of Toll. The intracytoplasmic adapter molecule Tube and the kinase Pelle interact through their conserved death domains, and act downstream of Toll on the cytoplasmic Dorsal-related immunity factor (DIF)-Cactus complex. Cactus is phosphorylated and degraded, and in consequence DIF, a member of the Rel family of transcription factors, translocates to the nucleus and activates the transcription of Drs (Tauszig-Delamasure, 2002 and references therein).
The response to Gram-negative bacterial infection in Drosophila is largely Toll independent. Toll-mutant flies resist infection by Escherichia coli, and upon challenge induce expression of the antibacterial peptides Drosocin and Diptericin, like wild-type flies. Expression of the antibacterial peptides in response to Gram-negative bacterial infection is controlled by the Imd (for immune deficiency) pathway, distinct from that of Toll (Tauszig-Delamasure, 2002 and references therein).
The discovery of the immune function of Toll in Drosophila led to the identification of the family of Toll-like receptors (TLRs) in mammals. Like Toll, TLRs combine an ectodomain composed of leucine-rich repeats and a signaling intracytoplasmic domain, the TIR domain (which is also present in the interleukin 1 (IL-1) receptor. Distinct mammalian TLRs are involved in the activation of immune cells by PAMPs such as lipopeptides, PGN or zymosan (TLR2), LPS (TLR4), the 2-kD mycobacterial-associated lipopeptide (MALP-2) (TLR6), unmethylated CpG DNA (TLR9) and flagellin (TLR5). Upon activation, TLRs signal to NF-kappaB through the adapter MyD88, which combines an NH2-terminal death domain and a COOH-terminal TIR domain. MyD88 interacts with TLRs through its conserved TIR domain, and also binds the Pelle-related IL-1 receptor-associated kinase (IRAK). Macrophages from MyD88-deficient mice do not produce cytokines such as tumor necrosis factor-alpha (TNF-alpha) in response to any TLR ligand; this observation provides the genetic proof that MyD88 integrates signals from distinct TLRs (Tauszig-Delamasure, 2002 and references therein).
It had been assumed until now that Tube is a functional equivalent of MyD88 in Drosophila, although direct interaction between Tube and Toll had not been detected. During analysis of the Drosophila genome, a gene encoding a MyD88-related molecule was identified. This raised the question of what function this molecule has in the host response. Drosophila Myd88 has been shown to be an essential component of the Toll pathway during the response to fungal and Gram-positive bacterial infection. In contrast, the response to Gram-negative infection is normal in Myd88-mutant flies (Tauszig-Delamasure, 2002).
The gene Myd88 is located on the right arm of the second chromosome, in band 45C4, and two P elements, EP(2)2535 and EP(2)2133, have been mapped to the 5' untranslated region of the gene. Northern blot analysis shows that the major Myd88 transcript is slightly reduced in size and intensity in flies homozygous for the EP(2)2535 insertion and is markedly reduced in flies homozygous for the EP(2)2133 insertion compared to wild-type flies. In the line with slight reduction of Myd88 expression [EP(2)2535], induction of Drs expression by the fungus Beauveria bassiana is similar to that in wild-type flies. In contrast, in the line showing marked reduction of Myd88 expression [EP(2)2133], induction of Drs by fungal infection is totally suppressed at 24 h and greatly reduced at 48 h. In this line, induction of Drs by septic injury with a mixture of Gram-positive and Gram-negative bacteria is also greatly reduced. Induction of Dpt, encoding the antibacterial peptide Diptericin, is not affected, however (Tauszig-Delamasure, 2002).
EP(2)2133 homozygous flies have a reduced resistance to infection by the fungus B. bassiana and the Gram-positive bacterium Streptococcus faecalis as compared to wild-type flies. The survival curves parallel those of flies mutated at the spz locus, encoding the putative Toll ligand Spaetzle. However, these flies are not sensitive to infection by E. coli, unlike the kenny mutant (encoded by key) of the Imd pathway. It is concluded that the Myd88 gene product is required for resistance to fungal and Gram-positive bacterial infection but not for resistance to Gram-negative bacterial infection (Tauszig-Delamasure, 2002).
The Drosophila response to Gram-negative bacterial infection is controlled by the Imd pathway. Several genes coding intracytoplasmic factors operating in the Imd pathway have been identified by genetic screens, but the PRRs triggering this cascade are not known. In mammals, TLR4 is essential in the response to LPS derived from E. coli, which suggests that Toll-related receptors might activate the Imd pathway in response to Gram-negative bacterial infection in Drosophila. The Drosophila genome encodes eight such receptors in addition to Toll; these genes are 18-wheeler (18W) and Toll-3 to Toll-9. Analysis of 18w-mutant adult flies has shown that this gene is not required for the Drosophila host defense against bacterial infection. Overexpression of gain-of-function versions of the other Tl-related genes (Tl-3 to Tl-9) in tissue culture cells is not sufficient to mimic the induction of antibacterial genes by LPS or E. coli. Because no mutants for Tl-3 to Tl-9 are presently available, it has not been possible to completely rule out that the possibility that these genes are involved in the immune response. However, in vivo data indicates that the Toll receptors function differently in mammals and in Drosophila. Indeed, in mice, MyD88 seems to integrate signals from all TLRs, and MyD88-deficient macrophages do not respond to ligands derived from Gram-positive or Gram-negative bacteria or from yeast (such as PGN, LPS or zymosan, respectively) that activate different TLRs. In Drosophila, however, Myd88 is not essential for the control of Gram-negative infection (Tauszig-Delamasure, 2002).
Thus, the current understanding of the immune response and Toll receptors in Drosophila does not favor the hypothesis that these receptors, like mammalian TLRs, participate in the induction of the immune response by sensing specific microbial-derived molecules. Rather, most Drosophila Toll-related genes may serve developmental functions, like Tl and 18w. The hypothesis that Toll-related proteins have distinct functions in insects and mammals is consistent with the observation that these two groups of proteins seem to have evolved independently (Tauszig-Delamasure, 2002).
The line EP(2)2133 (Myd88EP(2)2133) contains a P-element inserted in the non-coding region of the first exon of the Myd88 gene (Tauszig-Delamasure, 2002). These flies, like Toll mutant flies, are highly susceptible to infection by fungi or by Gram-positive bacteria. However, Myd88EP(2)2133 female flies are fertile, suggesting either that this insertion does not affect Myd88 expression in the embryo or that Myd88 is dispensable for the establishment of embryonic dorsoventral polarity. Myd88 messenger RNA is present in 0-2 h embryos, before zygotic expression begins, revealing the existence of a maternal contribution for this gene, as is true of the other genes of the Toll pathway (Kambris, 2003).
The Drosophila Myd88 gene is composed of five exons. The fifth exon encodes a C-terminal domain following the essential TIR domain. This extension is not present in mammalian MyD88. A large-scale mutagenesis was performed by mobilizing a piggyBac transposable element. By inverse polymerase chain reaction (PCR) and DNA sequencing of piggyBac insertion sites, a line was identified containing an insertion in the last intron of Myd88 (PBc03881). The level of Myd88 transcript is not affected in preblastoderm embryos from mothers homozygous for the PBc03881 insertion (Myd88PBc03881) or in Myd88PBc03881 adult flies, as opposed to the transcript in embryos from Myd88EP(2)2133 mothers, which is significantly reduced (Tauszig-Delamasure, 2002). However, reverse-transcriptase-mediated PCR (RT-PCR) experiments have revealed that the PBc03881 insertion interferes with the splicing of the Myd88 transcript, resulting in a chimaeric mRNA in which the last exon of Myd88 is replaced by exons 2, 3 and 4 of the white gene. This transcript encodes a truncated protein in which the C-terminal extension is replaced by 39 random amino acids (Kambris, 2003).
A determination was made of whether the Myd88PBc03881 homozygous adults present an immune phenotype similar to that of the previously characterized Myd88EP(2)2133 mutant strain (Tauszig-Delamasure, 2002). Induction of the drosomycin gene in response to infection by a mixture of Gram-positive and Gram-negative bacteria or by fungi is severely reduced in Myd88PBc03881 homozygous flies, and this phenotype can be rescued upon expression of a Myd88 complementary DNA through the UAS/Gal4 system. In agreement with these molecular data, Myd88PBc03881 homozygous flies are highly susceptible to infection by fungi and by Gram-positive bacteria. Thus, PBc03881 is a new mutant allele of Myd88. The deletion of the C-terminal extension, or the addition of 39 random amino acids, might destabilize the protein. Alternatively, the C-terminal extension of Myd88 might be required for the normal function of the protein. To test these possibilities, plasmids were constructed to express epitope-tagged versions of the wild-type protein and a truncated version containing only the death domain and the TIR domain. After transfection of S2 cells, both proteins could be detected by Western blotting, indicating that deletion of the C-terminal extension does not affect the stability of the protein. However, only overexpression of wild-type Myd88 led to the induction of a drosomycin reporter construct in transfected cells, indicating that the C-terminal extension is important for Myd88 function (Kambris, 2003).
Although Myd88PBc03881 homozygous flies develop normally, it was noticed that the females are sterile. The cuticles secreted by the embryos laid by Myd88PBc03881 homozygous females were analyzed and it was observed that filtzkörpers and ventral denticle belts were absent. These cuticular structures are representative of dorsolateral and ventral cell fates, respectively, and their absence is a characteristic feature of dorsalized embryos. In agreement with this observation, no nuclear localization of Dorsal on the ventral side of these mutant embryos was detected. In addition, in the same embryos, no expression of the Dorsal target gene twist was detected. These results indicate that Myd88 is required maternally for the establishment of the dorsoventral axis of the embryo. The fact that Myd88EP(2)2133 female flies are fertile implies that the level of maternal Myd88 transcript is not crucial for the developmental function of Myd88. To confirm that the PBc03881 insertion affects Myd88 function, several control experiments were undertaken: (1) the sterility of Myd88PBc03881 females could be complemented by the deficiency Df5423 (which does not uncover Myd88) but not by Df3591 (which uncovers Myd88), indicating that it resulted from the insertion of the transposon and not from a second-site mutation; (2) the piggyBac element was precisely excised and female fertility was restored; (3) it was possible to rescue the Myd88PBc03881 sterility phenotype by expressing a Myd88 cDNA in the female germline through the UAS/Gal4 system. Taken together, these data demonstrate that the sterility of Myd88PBc03881 homozygous female flies is a consequence of a mutation in Myd88. To determine whether Myd88 functions in the Toll pathway in the embryo, the Toll10B allele, which is a dominant gain-of-function allele of Toll, was used. Toll10B females generate ventralized embryos. Toll10B females homozygous for Myd88PBc03881 were found to produce dorsalized embryos indistinguishable from those laid by Myd88PBc03881 homozygous females. Moreover, embryos from Toll10B mothers express twist both dorsally and ventrally, whereas embryos from Myd88PBc03881;Toll10B double-mutant females do not express twist, like those from Myd88PBc03881 homozygous females. Thus, these data show that Myd88 is a component of the dorsal group of genes in the Toll pathway (Kambris, 2003).
Zygotes that lack Myd88 function develop to adults, indicating that Myd88 is not absolutely required zygotically. To determine whether homozygous Myd88PBc03881 flies have decreased viability, females carrying the PBc03881 insertion balanced with the CyO balancer were crossed to males of the same genotype or to males of the Df3591 or of the Df5423 deficiencies balanced with CyO. In the progeny of these crosses, the number of flies with straight wings (not CyO) were counted and the percentage of flies obtained compared with those expected was calculated. Homozygous Myd88PBc03881 flies and transheterozygotes for Myd88PBc03881 over Df3591 (Myd88-), but not over Df5423 (Myd88+), have a decreased likelihood of survival. Similar observations have been made in the case of tube and pelle, although no precise zygotic defect leading to lethality could be associated with mutations in these genes (Kambris, 2003).
In conclusion, a new function for the gene Myd88 has been uncovered -- its requirement for the establishment of the dorsoventral axis of Drosophila embryos. These results suggest that the intracytoplasmic Toll pathway is essentially the same in the early embryo and in adult fat body cells, with the notable exception of the transcription factor Dif, which is not required during embryogenesis but has a crucial role in the Toll-mediated response to fungal and Gram-positive bacterial infections. Myd88 had not been identified in the screens searching for genes on the second chromosome specifying the dorsoventral pattern. It is possible that these screens were not completely saturating and that other genes that might not have been identified include those encoding the factors that bridge the kinase Pelle to the inhibitor Cactus. The data also point to the importance of the C-terminal extension following the TIR domain. This extension is not present in the mammalian MyD88 but it is in mosquito MyD88. Further experiments will establish whether it affects the folding of the protein or its subcellular localization, or whether it mediates interaction with other components of the receptor complex (Kambris, 2003).
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date revised: 23 August 2017
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