InteractiveFly: GeneBrief

Toll-9: Biological Overview | References

Drosophila Toll-1 and all mammalian Toll-like receptors regulate innate immunity. However, the functions of the remaining eight Toll-related proteins in Drosophila are not fully understood. This study shows that Drosophila Toll-9 is necessary and sufficient for a special form of compensatory proliferation after apoptotic cell loss (undead apoptosis-induced proliferation [AiP]). Mechanistically, for AiP, Toll-9 interacts with Toll-1 to activate the intracellular Toll-1 pathway for nuclear translocation of the NF-κB-like transcription factor Dorsal, which induces expression of the pro-apoptotic genes reaper and hid. This activity contributes to the feedback amplification loop that operates in undead cells. Given that Toll-9 also functions in loser cells during cell competition, this study defines a general role of Toll-9 in cellular stress situations leading to the expression of pro-apoptotic genes that trigger apoptosis and apoptosis-induced processes such as AiP. This work identifies conceptual similarities between cell competition and AiP (Shields, 2022).

Since the discovery of the original Toll gene in Drosophila (Toll-1 hereafter), a large number of Toll-related genes have been identified in both insects and mammals. The Drosophila genome encodes a total of 9 Toll-related genes, including Toll-1, while mammalian genomes encode between 10 and 13 Toll-like receptors (TLRs). TLRs are single-pass transmembrane proteins that upon ligand stimulation usually trigger a conserved intracellular signaling pathway, culminating in the activation of NF-κB transcription factors. Initially identified as an essential gene for dorsoventral patterning in the early Drosophila embryo, Toll-1 was later also found to be a critical component for innate immunity. In this function, Toll-1 signaling via the NF-κB transcription factors Dorsal and Dorsal-related immunity factor (Dif) induces the expression of anti-microbial peptides (AMPs) that mediate innate immunity. A role in innate immunity has also been demonstrated for all mammalian TLRs. Likewise, Drosophila Toll-8 (aka Tollo) regulates immunity in the trachea. Toll-7 may regulate anti-viral responses, albeit through an NF-κB-independent mechanism. However, for the remaining Toll-related proteins in Drosophila, a function in innate immunity has not been clearly demonstrated (Shields, 2022).

Of particular interest is Toll-9 in Drosophila because it behaves genetically most similar to Toll-1 (Bettencourt, 2004; Ooi, 2002), and its intracellular TIR domain is most closely related to those of the mammalian TLRs (Khush, 2000; Ooi, 2002; Wasserman, 2000). Overexpression of Toll-9 results in the production of AMPs, which led to the proposal that Toll-9 might be involved in innate immunity (Ooi, 2002). However, a loss-of-function analysis with a defined Toll-9 null allele did not confirm this prediction (Narbonne-Reveau, 2011). Nevertheless, although Drosophila Toll-9 does not appear to be directly involved in regulating expression of AMPs, it has been implicated together with a few other Toll-related proteins in cell competition, an organismal surveillance program that monitors cellular fitness and eliminates cells of reduced fitness (losers). Depending on the type of cell competition, Toll-9 participates in the expression of the pro-apoptotic genes reaper and hid in loser cells, triggering their elimination . Therefore, it has been proposed that the function of Toll signaling for elimination of bacterial pathogens by AMPs and for elimination of unfit cells by pro-apoptotic genes bears a conceptual resemblance between innate immunity and cell competition (Shields, 2022).

Apoptosis is an evolutionarily well-conserved process of cellular suicide mediated by a highly specialized class of Cys-proteases, termed caspases. In Drosophila, the pro-apoptotic genes reaper and hid promote the activation of the initiator caspase Dronc (caspase-9 homolog in Drosophila). Dronc activates the effector caspases DrICE and Dcp-1 (caspase-3 and caspase-7 homologs), which trigger the death of the cell. However, caspases not only induce apoptosis but can also have non-apoptotic functions such as apoptosis-induced proliferation (AiP), during which caspases in apoptotic cells promote the proliferation of surviving cells independently of their role in apoptosis. Early work has shown that AiP requires the initiator caspase Dronc (Shields, 2022).

To reveal the mechanism of AiP, this study expressedthe pro-apoptotic gene hid and the apoptosis inhibitor p35 simultaneously using the ey-Gal4 driver (referred to as ey > hid,p35) which drives expression in the larval eye disc anterior to the morphogenetic furrow (MF) . p35 encodes a specific inhibitor of the effector caspases DrICE and Dcp-1 but does not block the activity of Dronc. In ey > hid,p35-expressing discs, the apoptotic pathway is activated by hid expression but blocked downstream because of DrICE and Dcp-1 inhibition by P35, rendering cells in an 'undead' condition. Although apoptosis is inhibited in undead tissue, AiP still occurs because of non-apoptotic signaling by the initiator caspase Dronc, triggering hyperplasia of the anterior portion of the larval eye imaginal discs at the expense of the posterior eye field, which is reduced in size. Combined, these effects result in overgrowth of the adult head capsule, but a reduction or even absence of the eyes in the adult animal (Shields, 2022).

Using the undead model, this study showed that AiP is mediated by extracellular reactive oxygen species (ROS) generated by the NADPH oxidase Duox. ROS trigger the recruitment of hemocytes, Drosophila immune cells most similar to mammalian macrophages, to undead imaginal discs. Hemocytes in turn release signals that stimulate JNK activity in undead cells, which then promotes AiP. In addition, JNK can also induce the expression of hid, thus setting up an amplification loop in undead cells which continuously signals for AiP (Shields, 2022).

Given that undead cells are abnormal cells with potentially altered cellular fitness and that signaling by Toll-related proteins surveilles cellular fitness, this study examined if signaling by Toll-9 has an important function for undead AiP. This study shows that Toll-9 is strongly up-regulated in undead cells and is necessary for the overgrowth of undead tissue. Overexpression of Toll-9 with p35 induces all hallmarks of undead AiP signaling, including Duox-dependent ROS generation, hemocyte recruitment and JNK signaling. Mechanistically, genetic evidence is provided for a heterologous interaction between Toll-9 and Toll-1, which engages the canonical Toll-1 signaling pathway to promote nuclear translocation of the NF-κB-like transcription factor Dorsal, which induces the expression of reaper and hid. This activity contributes to the establishment of the feedback amplification loop that signals continuously for AiP. In conclusion, although Toll-9 does not appear to have an important function in innate immunity, it appears to be involved in the expression of pro-apoptotic genes such as reaper and hid in stress situations such as cell competition and undead AiP (Shields, 2022).

Toll-9 is the most closely related Drosophila TLR compared with mammalian TLRs, but a biological function of Toll-9 has not been clearly defined. All mammalian TLRs are involved in innate immunity; therefore, the close homology has led to the prediction that Drosophila Toll-9 also participates in innate immunity (Ooi, 2002). However, in Toll-9 mutants, the basal as well as bacterially induced AMP production is not affected, leading to the conclusion that Toll-9 is not involved in innate immunity (Narbonne-Reveau, 2011). Nevertheless, instead of eliminating foreign pathogens, previous work has shown that Toll-9 together with several other Toll-related receptors participates in elimination of unfit cells during cell competition (Alpar, 2018; Meyer, 2014). This is achieved through the expression of the pro-apoptotic gene rpr. This study demonstrates that Toll-9 has a similar rpr- and hid-inducing function during AiP, thereby adding to the database of Toll-9 function (Shields, 2022).

To identify the mechanism by which Toll-9 participates in AiP, advantage was taken of the observation that misexpression of Toll-9 is sufficient to induce overgrowth of ey > p35 animals. There are multiple aspects of this phenotype that are worth being discussed. First, key for many of the observations presented in this paper is the presence of P35, a very efficient inhibitor of the effector caspases DrICE and Dcp-1. In the absence of P35, overexpression of Toll-9 does not induce any obvious phenotypes in eye discs or adult heads. The exact reason for this P35 dependence is currently unknown, but it has also been observed upon misexpression of other genes involved in AiP, such as Myo1D, Toll-1, and SpzAct. The only known function of P35 is to inhibit DrICE and Dcp-1. Therefore, one possible explanation for the P35 dependence is that these caspases cleave and inactivate an as yet unidentified component of the AiP network, possibly to block inappropriate AiP under normal conditions. In the presence of P35, the AiP-blocking activity of DrICE is inhibited and with the addition of an AiP-inducing stimulus such as misexpression of Toll-9, AiP is engaged and can trigger tissue overgrowth. Second, the data show that ectopic p35,Toll-9 co-expression triggers overgrowth through a similar mechanism as hid,p35 co-expression. This includes Dronc activation, Duox-generated ROS, hemocyte recruitment, and JNK activation. These similarities allow placing the function of Toll-9 into the AiP network (Shields, 2022).

Third, mis-expressed Toll-9 can genetically interact with Toll-1. This interaction results in nuclear translocation of Dorsal and is dependent on Myd88, Tube, and Pelle, all canonical components of the intracellular Toll-1 signaling pathway. Importantly, the nuclear translocation of Dorsal and the p35,Toll-9-induced overgrowth is also dependent on Toll-1, suggesting that the activation of the Myd88/Tube/Pelle pathway is directly triggered by Toll-1 and not by Toll-9. Mechanistically, Toll-9 may activate Toll-1 either directly through hetero-dimerization or mediated by additional factors. Future work will be necessary to identify the molecular mechanism of the Toll-9/Toll-1 interaction (Shields, 2022).

Fourth, the outcome of the Toll-9/Toll-1 interaction is the expression of the pro-apoptotic genes reaper and hid. Because Toll-9 expression is strongly up-regulated in undead cells, these data suggest that Toll-9-induced expression of reaper and hid in undead cells is setting up an amplification loop. The cause of the strong transcriptional upregulation of Toll-9 in undead cells is unknown, but it requires JNK activity. The Toll-9 amplification loop contributes to the strength of undead signaling during AiP and propels the overgrowth of the tissue (Shields, 2022).

Fifth, another important question is how Toll signaling becomes activated during AiP. Toll-1 is activated by the ligand Spatzle during embryogenesis and the immune response. Spz requires proteolytic processing for activation, which during the immune response is mediated by the Ser-protease Spatzle-processing enzyme (SPE). Consistently, SPE RNAi can suppress both the ey > p35,Toll-9INTRA and ey > hid,p35-induced overgrowth phenotypes. SPE RNAi suppressed ey > p35,Toll-9INTRA, which lacks the extracellular domain and should be insensitive to a ligand. Thus, the suppression of ey > p35,Toll-9INTRA suggests that SPE does not act through Toll-9 but instead on Toll-1. This result is consistent with a recent finding that Toll-9 RNAi cannot suppress apoptosis induced by a dominant active SPE (SPEAct) transgene (Alpar, 2018). Although that there is an unknown Toll-9 ligand cannot be ruled out, Toll-9 may not need to be activated by a ligand. Toll-9 naturally carries an amino acid substitution in the cysteine-rich extracellular domain similar to the gain-of-function Toll-11 mutant (Ooi, 2002; Schneider, 1991). Indeed, Toll-9 behaves as a constitutively active receptor in cell culture assays (Ooi, 2002). As TLRs can form homo- and heterodimers, it is possible that the constitutive activity of Toll-9 and the strong transcriptional upregulation of Toll-9 together with ligand stimulation of Toll-1 by Spz is sufficient for the activation of the Toll-1/Toll-9 complex. However, it remains unknown how SPE becomes activated during AiP (Shields, 2022).

With these considerations in mind, the following model for Toll-9 function during undead AiP emerges. The initial stimulus for AiP is the Gal4-induced expression of hid and p35, which leads to the activation of Dronc. Because of P35, Dronc cannot induce apoptosis but instead activates Duox for generation of ROS. ROS attract hemocytes which release signals for JNK activation in undead cells. JNK signaling directly or indirectly induces Toll-9 transcription. Up-regulated Toll-9 interacts with Toll-1, and after Spz ligation the Myd88/Tube/Pelle pathway triggers the nuclear accumulation of Dorsal and potentially Dif. These factors transcriptionally induce reaper and hid expression setting up the feedback amplification loop, which maintains and propels AiP and overgrowth (Shields, 2022).

One other interesting question to examine in the future will be how the intracellular pathway of Toll-1 signaling including Dorsal and Dif can induce different target genes under different conditions. For dorsoventral patterning of the Drosophila embryo, Dorsal induces the expression of twist and snail). During immune responses in the fat body, it promotes the expression of AMP genes as well as Kennedy pathway genes for the synthesis of phospholipids, while during cell competition and AiP which occur in larval imaginal discs, pro-apoptotic genes hid and rpr are induced. One potential answer to this question is that the specificity of Toll-1 signaling may be modified by the interaction with Toll-9. Although this interaction occurs at the plasma membrane, it also might influence the activity in the nucleus. It will also be interesting to examine if Toll-1 can interact with some or all of the other Toll-related receptors in Drosophila and how this interaction might influence the specificity of the transcriptional outcome. Although Toll-9 in Drosophila does not appear to be required for innate immunity, on the basis of its non-essential function to induce AMP production during bacterial infection (Narbonne-Reveau, 2011), the currenrt work and work by others (Meyer, 2014) reveals that Toll-9 may have a function during stress responses which involves expression of pro-apoptotic genes such as rpr and hid. That was demonstrated previously for cell competition and now for undead AiP, indicating potential similarities between cell competition and undead AiP. At first, such similarities appear to be at odds with the common dogmas that proliferating winner cells trigger apoptosis of loser cells, while during AiP, apoptotic cells induce proliferation of surviving cells. However, it has also been reported that loser cells have a much more active role during cell competition and can promote the winner status of cells with increased fitness. Therefore, there appear to be significant similarities between cell competition and undead AiP. The common denominator for both systems is the expression of pro-apoptotic genes. These responses have different outcomes in both systems. During cell competition, this response involves the death of the loser cells. During undead AiP, it sets up the amplification loop known to operate in undead cells, which propels hyperplasia and tissue overgrowth (Shields, 2022).

This work was performed largely under undead conditions (i.e., in the presence of the effector caspase inhibitor p35, which is not an endogenous gene in Drosophila). In reality, however, in the absence of p35, effector caspases are also activated in apoptotic cells, which will eventually lead to the death of the cell. Therefore, the question arises as to how apoptosis and AiP are linked to allow compensatory proliferation under normal conditions. Recently, evidence has been presented that certain apoptotic cells (dying enterocytes in the adult intestine) can adopt a transiently undead-like state that enables them to signal for AiP before they are dying and removed (Amcheslavsky, 2020 ). The transiently undead-like state is achieved by transient localization of Dronc to the plasma membrane, which might serve as a non-apoptotic compartment of the cell (Amcheslavsky et al., 2018 ; Bergmann, 2018 ). In that way, apoptotic cells, before they die, can trigger AiP in a p35-independent manner. Therefore, in future research, it will be important to examine if the Toll-9/Toll-1 interaction sets up a similar amplification loop in transiently undead enterocytes (Shields, 2022).

An ancient defense system eliminates unfit cells from developing tissues during cell competition

Developing tissues that contain mutant or compromised cells present risks to animal health. Accordingly, the appearance of a population of suboptimal cells in a tissue elicits cellular interactions that prevent their contribution to the adult. This study reports that this quality control process, cell competition, uses specific components of the evolutionarily ancient and conserved innate immune system to eliminate Drosophila cells perceived as unfit. Toll-related receptors (TRRs) and the cytokine Spatzle (Spz) lead to NFκB-dependent apoptosis. Null mutations in Toll-3, Toll-8, or Toll-9 suppress elimination of loser cells, increasing loser clone size and cell number per clone, but do not alter control clones. Diverse 'loser' cells require different TRRs and NFκB factors and activate distinct pro-death genes, implying that the particular response is stipulated by the competitive context. These findings demonstrate a functional repurposing of components of TRRs and NFkappaB signaling modules in the surveillance of cell fitness during development (Meyer, 2014).

Altogether, these results demonstrate that the conceptual resemblance between cell competition and innate immunity is matched with genetic and mechanistic similarities. Thus, cells within developing tissues that are recognized as mutant or compromised are competitively eliminated via a TRR- and NFκB-dependent signaling mechanism. Although similar core signaling components are activated in both processes, cell competition culminates in local expression of proapoptotic genes rather than systemic induction of antimicrobial genes. Because cell competition is initiated by the emergence of cells of different fitness than their neighbors in a tissue, it is surmised that the initiating signal is common to many competitive contexts. The genetic data leads to a proposal of a model for how this signal is detected and transduced. The results point to a role for Spz in signal detection, as it is a secreted protein that is required for the killing activity of competitive conditioned medium (cCM), is a known ligand for the Toll receptor, and is produced by several tissues in the larva. Thus, it is speculated that Spz functions as a ligand for one or more TRR in cell competition. Because Spz must be activated through a series of proteolytic steps, the relevant proteases may respond directly to the initiating signal in cell competition. It is proposed that the genetic identity or context of the competing populations influences activation of different TRR signaling modules and that the precise configuration of TRRs on loser cells dictates which of the three Drosophila NFκB proteins is activated. How signaling to the NFκBs is restricted to the loser cells is not known, but higher expression of Toll-2, Toll-8, and Toll-9 in loser cells could bias signal transduction. PGRP-LC, a receptor known to bind only bacterial products, also plays a role in Myc-induced competition. As commensal gut microflora is known to influence larval growth, this raises the possibility that it also contributes to the competitive phenotype (Meyer, 2014).

Throughout evolution, signaling modules have adapted to fulfill different functions even within the same species. This study has provided evidence for adaptation of TRR-NFκB signaling modules in an organismal surveillance system that measures internal tissue fitness rather than external stimuli. It is noteworthy that the killing of WT cells by supercompetitor cells is a potentially pathological form of cell competition that could propel expansion of premalignant tumor cells. If so, activated TRR-NFκB signaling modules in nonimmune tissues could be diagnostic markers, and their competitive functions could serve as therapeutic targets for cancer prevention (Meyer, 2014).

Lack of an antibacterial response defect in Drosophila Toll-9 mutant

Toll and Toll-like receptors represent families of receptors involved in mediating innate immunity response in insects and mammals. Although Drosophila proteome contains multiple Toll paralogs, Toll-1 is, so far, the only receptor to which an immune role has been attributed. In contrast, every single mammalian TLR is a key membrane receptor upstream of the vertebrate immune signaling cascades. The prevailing view is that TLR-mediated immunity is ancient. Structural analysis reveals that Drosophila Toll-9 is the most closely related to vertebrate TLRs and utilizes similar signaling components as Toll-1. This suggests that Toll-9 could be an ancestor of TLR-like receptors and could have immune function. Consistently, it has been reported that over-expression of Toll-9 in immune tissues is sufficient to induce the expression of some antimicrobial peptides in flies. These results have led to the idea that Toll-9 could be a constitutively active receptor that maintain significant levels of antimicrobial molecules and therefore provide constant basal protection against micro-organisms. To test theses hypotheses, this study generated and analyzed phenotypes associated with a complete loss-of-function allele of Toll-9. The results suggest that Toll-9 is neither required to maintain a basal anti-microbial response nor to mount an efficient immune response to bacterial infection (Narbonne-Reveau, 2011).

Toll and Toll-9 in Drosophila innate immune response

In both insects and mammals, members of the Toll receptor family play important roles in the initial events leading to the activation of immunity genes. The prototypic Toll in Drosophila appears to be activated by a host protein ligand after microbial stimulation. The cellular events and the biological response after Toll activation, however, require further investigation. This study used transgenic Drosophila strains expressing NF-kappaB and Toll proteins to investigate innate immune response in whole larvae and dissected larval fat bodies. Substantial activation of antimicrobial peptide genes was observed after septic injury. To circumvent the contribution of injury-induced response, dissected larval fat bodies were used to show that commercially available microbial compounds were able to alter the cellular distribution of Toll. The results also demonstrate that complex cellular events, including receptor trafficking, likely take place after stimulation of the larval immune tissue. By genome-wide expression analysis, it was further shown that Toll and Toll-9 may utilize the same signaling pathway in activating many immunity genes. Thus, the innate immune response in Drosophila is regulated by complex mechanisms, which involve Toll and other Toll-related proteins (Bettencort, 2004).

The Drosophila Toll-9, acting through Pelle and Cactus activates a constitutive antimicrobial defense

The Toll family of transmembrane proteins participates in signaling infection during the innate immune response. The nine Drosophila Toll proteins were analyzed and it was found that wild-type Toll-9 behaves similar to gain-of-function Toll-1. Toll-9 activates strongly the expression of Drosomycin, and utilizes similar signaling components to Toll-1 in activating the antifungal gene. The predicted protein sequence of Toll-9 contains a tyrosine residue in place of a conserved cysteine, and this residue switch is critical for the high activity of Toll-9. The Toll-9 gene is expressed in adult and larval stages prior to microbial challenge, and the expression correlates with the high constitutive level of drosomycin mRNA in the animals. The results suggest that Toll-9 is a constitutively active protein, and implies its novel function in protecting the host by maintaining a substantial level of antimicrobial gene products to ward off the continuous challenge of microorganisms (Ooi, 2002).

In both dorsal–ventral development and antifungal response, activated Toll-1 recruits Tube and Pelle to initiate signaling. Both Tube and Pelle contain death domains, and Pelle is a kinase. Recruitment of Pelle somehow leads to degradation of the inhibitor Cactus and release of the transcription factors, Dorsal and Dif. Whether Toll-9 employs the same signaling components to activate drosomycin expression was examined. A construct for Pelle containing only the death domain (Pelle^DD), but lacking the kinase domain, was generated. This mutated Pelle protein should function as dominant negative by binding to the death domain of Tube but cannot phosphorylate downstream substrates. Transfection of wild-type Pelle activated the reporter gene efficiently, consistent with an important role of the protein in antifungal response. As expected, Pelle^DD did not activate the reporter. In contrast, the Pelle^DD construct inhibited all the Toll-1-, Toll^10b- and Toll-9-mediated drosomycin reporter activities (Ooi, 2002).

Cactus uses its ankyrin repeats to bind to the Rel homology domains of Dif and Dorsal. The Cactus protein degradation is regulated both by signal dependent and signal independent mechanisms, through the N-terminal serine residues and C-terminal PEST sequence, respectively. Therefore, a construct CactusDelta¹²⁵Delta^PEST was used that contained only the ankyrin repeats. This mutant Cactus should stably bind to and inhibit Dif and Dorsal, even when the signaling pathway is stimulated. Co-transfection of wild-type Cactus did not lead to significant changes in the activation of drosomycin by Toll-1, Toll^10b and Toll-9. In contrast, the CactusDelta¹²⁵Delta^PEST construct abolished all these Toll signaling activities. Therefore, Cactus and Pelle, and probably the binding partners Dif and Tube, are likely signaling components that mediate the activation of drosomycin by Toll-9 (Ooi, 2002).

Search PubMed for articles about Drosophila Toll-9

Alpar, L., Bergantinos, C. and Johnston, L. A. (2018). Spatially Restricted Regulation of Spatzle/Toll Signaling during Cell Competition. Dev Cell 46(6): 706-719 e705. PubMed ID: 30146479

Amcheslavsky, A., Lindblad, J. L. and Bergmann, A. (2020). Transiently "Undead" Enterocytes Mediate Homeostatic Tissue Turnover in the Adult Drosophila Midgut. Cell Rep 33(8): 108408. PubMed ID: 33238125

Bettencourt, R., Tanji, T., Yagi, Y. and Ip, Y. T. (2004). Toll and Toll-9 in Drosophila innate immune response. J Endotoxin Res 10(4): 261-268. PubMed ID: 15373972

Herrera, S. C. and Bach, E. A. (2018). Super-Competitors Game the Fitness Sensing System. Dev Cell 46(6): 672-674. PubMed ID: 30253165

Khush, R. S. and Lemaitre, B. (2000). Genes that fight infection: what the Drosophila genome says about animal immunity. Trends Genet 16(10): 442-449. PubMed ID: 11050330

Meyer, S. N., Amoyel, M., Bergantinos, C., de la Cova, C., Schertel, C., Basler, K. and Johnston, L. A. (2014). An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346: [Epub ahead of print]. PubMed ID: 25477468

Narbonne-Reveau, K., Charroux, B. and Royet, J. (2011). Lack of an antibacterial response defect in Drosophila Toll-9 mutant. PLoS One 6: e17470. PubMed ID: 21386906

Ooi, J. Y., Yagi, Y., Hu, X. and Ip, Y. T. (2002). The Drosophila Toll-9 activates a constitutive antimicrobial defense. EMBO Rep 3: 82-87. PubMed ID: 11751574

Shields, A., Amcheslavsky, A., Brown, E., Lee, T. V., Nie, Y., Tanji, T., Ip, Y. T. and Bergmann, A. (2022). Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila. Cell Rep 39(7): 110817. PubMed ID: 35584678

Wasserman, S. A. (2000). Toll signaling: the enigma variations. Curr Opin Genet Dev 10(5): 497-502. PubMed ID: 10980426

date revised: 7 November, 2022

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