Gay Dominant Tube

Gay Dominant Tube

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pelle DEVELOPMENTAL BIOLOGY Embryonic Cytoplasmic injection experiments have shown that Pelle function suppled as late as stage 4 of embryonic development (the syncytial blastoderm stage) can rescue a maternal deficiency of Pelle. After stage 4 the Pelle activity is no longer present, and efficient embryos lose their ability to respond to injected Pelle at this point (Müller-Holtkamp, 1985). Effects of Mutation or Deletion Mutations in the kinase domain abolish pelle function. Mutations were generated in oligonucleotides and tested by injecting mutant mRNA into embryos laid by pll mutant females. Mutation in the putative active site of the kinase domain destroys its ability to rescue a pelle mutation (Shelton, 1993).tube and pelle are two maternally transcribed genes required for dorsal-ventral patterning inthe Drosophila embryo. Females homozygous for strong alleles of tube or pelle produce embryosthat lack all ventral and lateral embryonic pattern elements. Double mutant females carrying dominant ventralizing alleles of Toll anddorsalizing alleles of tube or pelle produce dorsalized embryos, suggesting that tube and pelle actdownstream of the membrane protein Toll in the signaling pathway that defines the embryonicdorsal-ventral pattern. Both tube and pelle are also important zygotically for survival. At least 30%of the zygotes lacking either tube or pelle die before adult stages, while 90-95% of tube- pelle-double mutant zygotes die (Hecht, 1993). Two components are known to mediate thesignal transduction between Toll and Dorsal-Cactus: Pelle, a serine/threonine protein kinase, andTube, a protein with an unknown biochemical activity. Gain-of-function alleles ofpelle and tube show that pelle functions downstream of tube. In addition, Pelle and Tubeinteract directly with one another. Tube is probably a direct activator of the protein kinasePelle (Grosshans, 1994).The Toll signaling pathway functions in several Drosophila processes, including dorsal-ventral pattern formation andthe immune response. This pathway is required in the epidermis for proper muscledevelopment. Because Toll mutations affect the development of all 30 muscle fibers in each hemisegment, and not just the several that express Toll, or those closest to the CNS, it semed likely that the epidermal expression is most relevant to muscle development. In the epidermis, Toll expression is highest in the epidermal muscle attachment (EMA) cells, aligned along the segment border; these cells are known to play an important role in muscle patterning. The zygotic Toll protein is necessary for normal muscle development; in theabsence of zygotic Toll, close to 50% of hemisegments have muscle patterning defects consisting of missing,duplicated and misinserted muscle fibers (Halfon, 1998).The requirements for easter, spatzle, tube, and pelle, all of whichfunction in the Toll-mediated dorsal-ventral patterning pathway have now been analyzed. spatzle, tube, and pelle, but not easter,are necessary for muscle development. Mutations in these genes give a phenotype identical to that seen in Tollmutants, suggesting that elements of the same pathway used for Toll signaling in dorsal-ventral development are used during muscle development. By expressing the Toll cDNA under the control of distinct Toll enhancer elements in Toll mutant flies, the spatial requirements for Toll expression were examined during muscle development. Expression of Toll in a subset of epidermal cells that includes the epidermal muscle attachment cells, but not Toll expression in the musculature, is necessary for proper muscle development. A 6.5-kb enhancer element drives expression solely in mesodermally derived tissues. A 1.4-kb enhancer drives expression in the epidermis, CNS midline, gut, salivary glands, Malpighian tubules, pharynx and esophagus, but not in mesodermal tissues. These two enhancers were used to drive expression of Toll in transgenic flies. The 1.4-kb enhancer express Toll in the epidermis (in a narrow strip of cells that includes the EMA cells) as well as in a cluster of cells in the lateral, mid-bodywall region of each segment. This lateral region contains the cells where the lateral transverse muscle fibers have their insertions. Flies with 1.4-kb enhancer driven Toll expression show complete rescue of the muscle error phenotype. These results suggest that signals received by the epidermisearly during muscle development are an important part of the muscle patterning process (Halfon, 1998). Although loss of single minded, a regulator of the Toll pathway in the central midline, causes positioning and insertion errors in a group of the most ventral muscles, these defects are qualitatively different from those observed in Toll mutants. The errors due to sim mutation are thus not likely due to loss of Toll expression; Toll expression in the midline appears to be uninvolved in muscle patterning. It is known that signaling from the muscle fibers induces the expression of beta1-tubulin in the EMA cells and regulates the maintenance of expression of other attachment site-specific genes such as delilah, groovin, and stripe. The nature of the Toll muscle phenotype (most of which consists of duplicated and deleted muscle fibers) suggests that Toll may be acting early in the development process, during the time of founder specification or early muscle fiber growth. The remaining errors (those in muscle insertion) may be either early or late in origin: they may be secondary to mis-specification of muscle identity (early), or alternatively, might indicate a further requirement for Toll during the insertion process (late) (Halfon, 1998). There are a number of different controls on the expression of the antifungal polypeptide gene drosomycin in adults: the receptor Toll, intracellular components of the dorsoventral signaling pathway (Tube, Pelle, and Cactus), and the extracellular Toll ligand, Spätzle, but not the NF-kappaB related transcription factor Dorsal. Mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. In Tl-deficient adults, the cecropin A and, to a lesser extent, attacin, drosomycin and defensin genes are only minimally inducible, in contrast with the diptericin and drosocin genes, which remain fully inducible in this context. The drosomycin gene induction is not affected in mutants deficient in gastrulation defective, snake and easter, all upstream of spätzle in the dorsoventral pathway. The involvement of Spätzle in the drosomycin induction pathway is unexpected, since, in contrast with cat, pll, tub, and Tl, the spz mutant shows no striking zygotic phenotype. The partner of Cact in the drosomycin induction pathway has not yet been identified, but it is probably a member of the Rel family, possibly Dorsal-related immunity factor (Lemaitre, 1996).There are two distinct regulatory pathways controlling the expression of antimicrobial genes, the dorsoventral pathway and the immune deficiency (imd) gene. In contrast to the results with drosomycin, antibacterial genes, cecropin A1, diptericin, drosocin, attacin, and defensin do not give strong constitutive expression in dorsoventral pathway mutants. However, the level of constitutive expression of anti-bacterial genes in dorsoventral pathway mutants is higher than the basal level, and induction of Cecropin A genes is 4-fold lower in dorsoventral pathway mutants. The transcription of cact, dorsal, dif, pll, tub, Tl and spz genes, but not tub, are clearly up-regulated in response to immune challenge. Even though the same components of the dorsoventral pathway that are involved in antifungal response are also involved in antibacterial response, there is an additional requirement for the as yet uncloned imd gene product (Lemaitre, 1996). Differential activation of the Toll receptor leads to the formation of a broad Dorsal nuclear gradient that specifies at least three patterning thresholds of gene activity along the dorsoventral axis of precellularembryos. The activities of the Pelle kinase and Twist basic helix-loop-helix (bHLH) transcription factor in transducing Toll signaling have been investigated. Pelle functions downstream of Toll to release Dorsal from the Cactus inhibitor. Twist is an immediate-early gene that is activated upon entry of Dorsal into nuclei. Transgenes misexpressing Pelle and Twist were introduced into different mutant backgrounds and the patterning activities werevisualized using various target genes that respond to different thresholds of Toll-Dorsal signaling. These studies suggest that ananteroposterior gradient of Pelle kinase activity is sufficient to generate all known Toll-Dorsal patterning thresholds and that Twist canfunction as a gradient morphogen to establish at least two distinct dorsoventral patterning thresholds. How the Dorsal gradientsystem can be modified during metazoan evolution is discussed and it is concluded that Dorsal-Twist interactions are distinct from the interplay betweenBicoid and Hunchback, which pattern the anteroposterior axis (Stathopoulos, 2002).The snail, sim, vnd and sog expression patterns represent four different Toll-Dorsal signaling thresholds. snail is activated only by peak levels of the Dorsal gradient; sim and vnd are activated by intermediate levels, and sog is activated by the lowest levels of the gradient. These expression patterns were visualized in mutant and transgenic embryos via in situ hybridization using digoxigenin-labeled antisense RNA probes (Stathopoulos, 2002).Dorsal target genes are essentially silent in mutant embryos that lack an endogenous dorsoventral Dorsal nuclear gradient. Mutant embryos were collected from females that are homozygous for a null mutation in the gastrulation defective (gd) gene, which blocks the processing of the Spätzle ligand and the activation of the Toll receptor. These mutants permit the analysis of ectopic, anteroposterior Dorsal and Twist gradients in 'apolar' embryos that lack dorsoventral polarity. snail, vnd, and sog are sequentially expressed along the anteroposterior axis of mutant embryos that contain a constitutively activated form of the Toll receptor (Toll10b) misexpressed at the anterior pole using the bicoid (bcd) promoter and 3' UTR. These expression patterns depend on an ectopic anteroposterior Dorsal nuclear gradient. The repression of the vnd and sog patterns at the anterior pole is probably mediated by Snail, which normally excludes expression of these genes in the ventral mesoderm of wild-type embryos (Stathopoulos, 2002).The activated Pelle-Tor4021 kinase also directs sequential anteroposterior patterns of snail, vnd, and sog expression in gd–/gd– mutant embryos. As in the case of Toll10b, the activated Pelle kinase was misexpressed at the pole using the bcd 3' UTR. The snail, vnd and sog expression patterns are similar to those obtained with the Toll10b transgene. The vnd and sog expression patterns are probably repressed at the anterior pole by Snail. These results suggest that the levels of Pelle kinase activity are sufficient to determine different Dorsal transcription thresholds (Stathopoulos, 2002).Similar experiments were carried out with a Pelle-Tor fusion gene that contains the Tor signal peptide, extracellular domain and transmembrane peptide, but lacks the amino acid substitution (Y327C) in the Tor4021 protein that induces dimerization. The Pelle-Tor fusion protein fails to induce snail expression, but succeeds in activating vnd and sog (Stathopoulos, 2002). REFERENCES Cantera, R., Kozlova, T. Barillas-Mury, C. and Kafatos, F. C. (1999) Muscles and innveravtion are affected by loss of Dorsal in the fruit fly, Drosophila melanogaster. Mol. Cell. Neurosci. 13: 131-141. Medline abstract: 10192771Cao, Z., Henzel, W. J. and Gao, X. (1996). IRAK: a kinase associated with the interleukin-1 receptor. Science 271: 1128-31Charatsi, I., et al. (2003). Krapfen/dMyd88 is required for the establishment of dorsoventral pattern in the Drosophila embryo. Mech. Dev. 120: 219-226. 12559494 Edwards, D. N., Towb, P. and Wasserman, S. A. (1997). An activity-dependent network of interactions links the Rel protein Dorsal with its cytoplasmic regulators. Development 124(19): 3855-3864. Galindo, R. L., et al. (1995). Interaction of the pelle kinase with themembrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development 121: 2209-2218 Gillespie, S. K. and Wasserman, S. A. (1994). Dorsal, a Drosophila Rel-like protein, is phosphorylated upon activation of the transmembrane protein Toll. Mol. Cell. Biol. 14: 3559-68Grosshans, J., et al. (1994). Activation of the kinase Pelle by Tube in the dorsoventralsignal transduction pathway of Drosophila embryo. Nature 372: 563-566 Grosshans, J., Schnorrer, F. and Nusslein-Volhard, C. (1999). Oligomerisation of Tube and Pelle leads to nuclear localisation of dorsal. Mech. Dev. 81(1-2): 127-38. Halfon, M. S. and Keshishian, H. (1998). The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo. Dev. Biol. 199(1): 164-174. Heckscher, E. S., et al. (2007). NF-kappaB, IkappaB, and IRAK control glutamate receptor density at the Drosophila NMJ. Neuron 55: 859-873. Medline abstract: 17880891 Hecht, P. M. and Anderson, K. V. (1993). Genetic characterization of tube and pelle, genes required for signaling between Toll and dorsal in the specification of the dorsal-ventral pattern of the Drosophila embryo. Genetics 135: 405-17 Horng, T. and Medzhitov, R. (2001). Drosophila MyD88 is an adapter in the Toll signaling pathway. Proc. Natl. Acad. Sci. 98: 12654-12658. 11606776 Janssens, S., et al. (2002). Regulation of Interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88Curr. Biol. 12: 467-471. 11909531 Kobayashi, K., et al. (2002). IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110: 191-202. 12150927 Lemaitre, B., et al. (1996). The Dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973-983Moncrieffe, M. C., Stott, K. M. and Gay, N. J. (2005). Solution structure of the isolated Pelle death domain. FEBS letters 579: 3920-3926. 16004997 Müller-Holtkamp, F., et al. (1985). An early role of maternal mRNA in establishing the dorsoventral pattern in pelle mutant Drosophila embryos. Dev Biol 110: 238-46Muzio M., et al. (1997). IRAK (Pelle) family member IRAK-2 and MyD88 as proximalmediators of IL-1 signaling. Science 278(5343): 1612-1615. Norris, J. L. and Manley, J. L. (1996). Functional interactions between the pelle kinase, Toll receptor, and Tube suggest a mechanism for activation of Dorsal. Genes Dev. 10(7): 862-72. 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. 11751574 Reach, M., et al. (1996). A gradient of Cactus protein degradation establishes dorsoventral polarity in the Drosophila embryo. Dev. Biol. 180: 353-364Shelton, C. A. and Wasserman, S. A. (1993). pelle encodes a protein kinase required to establishdorsoventral polarity in the Drosophila embryo. Cell 72: 515-25Shen, B. and Manley, J. L. (1998). Phosphorylation modulates direct interactions between the Toll receptor,Pelle kinase and Tube. Development 125: 4719-4728. 9806920 Shen, B., et al. (2001). Physical and functional interactions between Drosophila TRAF2 and Pelle kinase contribute to Dorsal activation. Proc. Natl. Acad. Sci. 98: 8596-8601. 11447260 Shen, B. and Manley, J. L. (2002). Pelle kinase is activated by autophosphorylation during Toll signaling in Drosophila. Development 129: 1925-1933. 11934858 Stathopoulos, A. and Levine, M. (2002). Linear signaling in the Toll-Dorsal pathway of Drosophila: activated Pelle kinase specifies all threshold outputs of gene expression while the bHLH protein Twist specifies a subset. Development 129: 3411-3419. 12091311 Sun, H., et al. (2002). A heterotrimeric death domain complex in Toll signaling. Proc. Natl. Acad. Sci. 99: 12871-12876. 12351681 Takaesu, G., et al. (2001). Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway. Mol. Cell. Biol. 21(7): 2475-84. 11259596 Tauszig-Delamasure, S., et al. (2002). Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nat. Immunol. 3(1): 91-7. 11743586 Towb, P., Galindo, R. L. and Wasserman, S. A. (1998). Recruitment of Tube and Pelle to signaling sites at the surface of the Drosophila embryo. Development 125: 2443-2450. Towb, P., Bergmann, A. and Wasserman, S. A. (2001). The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development 128: 4729-4736. 11731453 Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. and Cao, Z. (1997). MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837-847. 9430229 Wu, C., Chen, Y., Wang, F., Chen, C., Zhang, S., Li, C., Li, W., Wu, S. and Xue, L.(2015). Pelle modulates dFoxO-mediated cell death in Drosophila. PLoS Genet 11:e1005589. PubMed ID: 26474173Xiao, T., et al. (1999). Three-dimensional structure of a complex between thedeath domains of Pelle and Tube. Cell 99: 545-555.Yang, J. and Steward, R. (1997). A multimeric complex and the nuclear targeting of the Drosophilarel protein Dorsal. Proc. Natl. Acad. Sci. 94(26): 14524-14529. Zapata, J. M., et al. (2000). The Drosophila Tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NFkappbB activity. J. Biol. Chem. 275: 12102-12107. 10766844 pelle: Biological Overview Evolutionary Homologs Regulation Developmental Biology Effects of Mutation 59ce067264

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