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JOURNAL ARTICLES
A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis
P. Qiu, P.C. Pan, S. Govind
Development 1998 125: 1909-1920;

Summary

In the Drosophila larva, blood cells or hemocytes are formed in the lymph gland. The major blood cell type, called plasmatocyte, is small, non-adhesive and phagocytic. Plasmatocytes differentiate into adhesive lamellocytes to form multilayered capsules around foreign substances or, in mutant melanotic tumor strains, around self tissue. Mutations in cactus or Toll, or constitutive expression of dorsal can induce lamellocyte differentiation and cause the formation of melanotic capsules. As maternally encoded proteins, Toll, Cactus and Dorsal, along with Tube and Pelle, participate in a common signal transduction pathway to specify the embryonic dorsal-ventral axis. Using the maternal pathway as a paradigm, we investigated if these proteins have additional roles in larval hemocyte formation and differentiation. Analysis of cactus mutants that lack Cactus protein revealed that almost all of these animals have an overabundance of hemocytes, carry melanotic capsules and die before reaching pupal stages. In addition, the lymph glands of cactus larvae are considerably enlarged. The number of mitotic cells in the cactus and TollD hemolymph is higher than that in the wild-type hemolymph. The hemocyte density of mutant Toll, tube or pelle hemolymph is significantly lower than that of the wild type. Lethality of mutant cactus animals could be rescued either by the selective expression of wild-type Cactus protein in the larval lymph gland or by the introduction of mutations in Toll, tube or pelle. Cactus, Toll, Tube and Pelle proteins are expressed in the nascent hemocytes of the larval lymph gland. Our results suggest that the Toll/Cactus signal transduction pathway plays a significant role in regulating hemocyte proliferation and hemocyte density in the Drosophila larva. These findings are discussed in light of similar hematopoietic functions of Rel/I(kappa)B-family proteins in mice.

REFERENCES

    1. Baeuerle P. A.,
    2. Baltimore D.
    (1996) NF-B: Ten years after. Cell 87, 13–20
    OpenUrlCrossRefPubMedWeb of Science
    1. Baldwin A. S., Jr
    (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Ann. Rev. Immunol 14, 649–683
    OpenUrlCrossRefPubMedWeb of Science
    1. Ballard D. W.,
    2. Walker W. H.,
    3. Doerre S.,
    4. Sista P.,
    5. Molitor J. A.,
    6. Dixon E. P.,
    7. Peffer N. J.,
    8. Hannink M.,
    9. Greene W. C.
    (1990) The v-rel oncogene encodes aB enhancerbinding protein that inhibits NF- B function. Cell 63, 803–814
    OpenUrlCrossRefPubMedWeb of Science
    1. Beg A. A.,
    2. Sha W. C.,
    3. Bronson R. T.,
    4. Baltimore D.
    (1995) Constitutive NF-B activation, enhanced granulopoiesis, and neonatal lethality in I B-deficient mice. Genes Dev 9, 2736–2746
    OpenUrlAbstract/FREE Full Text
    1. Beg A. A.,
    2. Baltimore D.
    (1996) An essential role for NF-B in preventing TNF- induced cell death. Science 274, 782–784
    OpenUrlAbstract/FREE Full Text
    1. Belvin M. P.,
    2. Jin Y.,
    3. Anderson K. V.
    (1995) Cactus protein degradation mediates Drosophila dorsal-ventral signaling. Genes Dev 9, 783–793
    OpenUrlAbstract/FREE Full Text
    1. Belvin M. P.,
    2. Anderson K. V.
    (1996) A conserved signaling pathway: the Drosophila Toll-Dorsal pathway. Annu. Rev. Cell. Dev. Biol 12, 393–416
    OpenUrlCrossRefPubMedWeb of Science
    1. Bergmann A.,
    2. Stein D.,
    3. Geisler R.,
    4. Hagenmaier S.,
    5. Schmid B.,
    6. Fernandez N.,
    7. Schnell B.,
    8. Nusslein-Volhard C.
    (1996) A gradient of cytoplasmic Cactus degradation establishes the nuclear localization gradient of the Dorsal morphogen in Drosophila. Mech. Devel 60, 109–123
    OpenUrlCrossRefPubMedWeb of Science
    1. Brand A. H.,
    2. Perrimon N.
    (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415
    OpenUrlAbstract
    1. Chadee D. N.,
    2. Taylor W. R.,
    3. Hurta R. A. R.,
    4. Allis C.D.,
    5. Wright J. A.,
    6. Davies J. R.
    (1995) Increased phosphorylation of histone H1 in mouse fibroblasts transformed with oncogenes or constitutively active mitogen-protein kinase. J. Biol. Chem 270, 20098–20105
    OpenUrlAbstract/FREE Full Text
    1. Chasan R.,
    2. Anderson K. V.
    (1989) The role of Easter, an apparent serine protease, in organizing the dorsal-ventral pattern of the Drosophila embryo. Cell 56, 391–400
    OpenUrlCrossRefPubMedWeb of Science
    1. DeLotto R.,
    2. Speirer P.
    (1989) A gene required for the specification of dorsal-ventral pattern in Drosophila appears to encode a serine protease. Nature 323, 688–692
    1. Fessler L. I.,
    2. Nelson R. E.,
    3. Fessler J. H.
    (1994) Drosophila extracellular matrix. Methods Enzymol 245, 271–294
    OpenUrlCrossRefPubMed
    1. Gateff E.
    (1978) Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200, 1448–1459
    OpenUrlAbstract/FREE Full Text
    1. Gateff E.
    (1994) Tumor-suppressor genes, hematopoietic malignancies and other hematopoietic disorders of Drosophilamelanogaster. Ann. NY Acad. Sci 712, 260–279
    OpenUrlCrossRefPubMedWeb of Science
    1. Geisler R.,
    2. Bergmann A.,
    3. Hiromi Y.,
    4. Nusslein-Volhard C.
    (1992) cactus, a gene involved in dorsoventral pattern formation of Drosophila is related to the I-kappa B gene family of vertebrates. Cell 71, 613–621
    OpenUrlCrossRefPubMedWeb of Science
    1. Gerttula S.,
    2. Jin Y.,
    3. Anderson K. V.
    (1988) Zygotic expression and activity of the DrosophilaToll gene, a gene required maternally for embryonic dorsal-ventral pattern formation. Genetics 119, 123–133
    OpenUrlAbstract/FREE Full Text
    1. Gross I.,
    2. Georgel P.,
    3. Kappler C.,
    4. Reichhart J.-M.,
    5. Hoffmann J. A.
    (1996) Drosophila immunity: a comparative analysis of the Rel proteins Dorsal and Dif in the induction of genes encoding diptericin and cecropin. Nucl. Acids Res 89, 7861–7865
    OpenUrl
    1. Grosshans J.,
    2. Bergmann A.,
    3. Haffter P.,
    4. Nusslein-Volhard C.
    (1994) Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo. Nature 372, 563–566
    OpenUrlCrossRefPubMedWeb of Science
    1. Harrison D. A.,
    2. Binari R.,
    3. Stines Nahreini T.,
    4. Gilman M.,
    5. Perrimon N.
    (1995) Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J 14, 2857–2865
    OpenUrlPubMedWeb of Science
    1. Hashimoto C.,
    2. Gerttula S.,
    3. Anderson K. V.
    (1991) Plasma membrane localization of the Toll protein in the syncytial Drosophila embryo: importance of transmembrane signaling for dorsal-ventral pattern formation. Development 111, 1021–1028
    OpenUrlAbstract/FREE Full Text
    1. Hecht P. M.,
    2. 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, 405–417
    OpenUrlAbstract/FREE Full Text
    1. Ip T. Y.,
    2. Reach M.,
    3. Engström Y.,
    4. Kadalayil L.,
    5. Cai H.,
    6. Gonzalez-Crespo S.,
    7. Tatei K.,
    8. Levine M.
    (1993) Dif, a dorsal -related gene that mediates an immune response in Drosophila. Cell 75, 753–763
    OpenUrlCrossRefPubMedWeb of Science
    1. Kidd S.
    (1992) Characterization of the Drosophilacactus locus and analysis of interactions between cactus and dorsal proteins. Cell 71, 623–635
    OpenUrlCrossRefPubMedWeb of Science
    1. Kontgen F.,
    2. Grumont R. J.,
    3. Strasser A.,
    4. Metcalf D.,
    5. Li R.,
    6. Tarlintin D.,
    7. Gerondakis S.
    (1995) Mice lacking the c- rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity and interleukin-2 expression. Genes Dev 9, 1965–1977
    OpenUrlAbstract/FREE Full Text
    1. Konrad K.,
    2. Marsh L.
    (1990) The gastrulation defective gene displays homology to serine proteases. In 31st Annual Drosophila Research Conference.
    1. Lehming N.,
    2. MCGuire S.,
    3. Brickman J. M.,
    4. Ptashne M.
    (1995). Interactions of a Rel protein with its inhibitor. Proc. Natl. Acad. Sci. USA 92, 10242–10246
    OpenUrlCrossRefPubMedWeb of Science
    1. Lemaitre B.,
    2. Nicolas E.,
    3. Michaut L.,
    4. Reichhart J.-M.,
    5. Hoffmann J. A.
    (1996) The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983
    OpenUrlAbstract/FREE Full Text
    1. Letsou A.,
    2. Alexander S.,
    3. Orth K.,
    4. Wasserman S. A.
    (1991) Genetic and molecular characterization of tube, a Drosophila gene, maternally required for embryonic dorsoventral polarity. Proc. Natl. Acad. Sci. USA 88, 810–814
    OpenUrlPubMedWeb of Science
    1. Letsou A.,
    2. Alexander S.,
    3. Wasserman S. A.
    (1993) Domain mapping of tube, a protein essential for dorsoventral patterning of the Drosophila embryo. EMBO J 12, 3449–3458
    OpenUrlPubMedWeb of Science
    1. Lu M. J.,
    2. Dadd C. A.,
    3. Mizzen C. A.,
    4. Perry C. A.,
    5. McLachlan D. R.,
    6. Annunziato A. T.,
    7. Allis C. D.
    (1994) Generation and characterization of novel antibodies highly selective for phosphorylated linker histone H1 in Tetrahymena and HeLa cells. Chromosoma 103, 111–121
    OpenUrlPubMedWeb of Science
    1. Luo H.,
    2. Hanratty W. P.,
    3. Dearolf C. R.
    (1995) An amino acid substitution in the Drosophila hopTum-lJak kinase causes leukemia-like hematopoietic defects. EMBO J 14, 1412–1420
    OpenUrlCrossRefPubMedWeb of Science
    1. Medzhitov R.,
    2. Preston-Hurlburt P.,
    3. Janeway C. A.
    (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397
    OpenUrlCrossRefPubMedWeb of Science
    1. Morisato D.,
    2. Anderson K. V.
    (1994) The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorso-ventral pattern of the Drosophila embryo. Cell 76, 677–688
    OpenUrlCrossRefPubMedWeb of Science
    1. Neri A.,
    2. Chang C.-C.,
    3. Lombardi L.,
    4. Salina M.,
    5. Corradini P.,
    6. Maiolo A. T.,
    7. Chaganti R. S. K.,
    8. Dalla-Favera R.
    (1991) B celllymphoma-associatedchromosomaltranslocation involves candidate oncogene lyt-10, homologous to NF-B p50. Cell 67, 1075–1087
    OpenUrlCrossRefPubMedWeb of Science
    1. Neuman-Silberberg F. S.,
    2. Schupbach T.
    (1993) The Drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGF-like protein. Cell 75, 165–174
    OpenUrlCrossRefPubMedWeb of Science
    1. Reach M.,
    2. Galindo R. L.,
    3. Towb P.,
    4. Allen J. L.,
    5. Karin M.,
    6. Wasserman S.A.
    (1996) A gradient of Cactus protein degradation establishes dorsoventral polarity in the Drosophila embryo. Dev. Biol 180, 353–364
    OpenUrlCrossRef
    1. Rizki T. M.
    (1957) Alterations in the hemocyte population of Drosophila melanogaster. J. Morphol 100, 437–458
    OpenUrlCrossRefWeb of Science
    1. Rizki T. M.,
    2. Rizki R. M.
    (1980) Properties of the larval hemocytes of Drosophila melanogaster. Experientia 36, 1223–1226
    OpenUrlCrossRefPubMedWeb of Science
    1. Roth S.,
    2. Stein D.,
    3. Nusslein-Volhard C.
    (1989) A gradient of nuclear localization of the dorsal protein determines dorsoventral pattern in the Drosophila embryo. Cell 59, 1189–1202
    OpenUrlAbstract
    1. Roth S.,
    2. Hiromi Y.,
    3. Godt D.,
    4. Nusslein-Volhard C.
    (1991) cactus, a maternal gene required for proper formation of the dorsoventral morphogen gradient in Drosophila embryos. Development 112, 371–388
    OpenUrlAbstract/FREE Full Text
    1. Rubin G. M.,
    2. Spradling A. C.
    (1982) Genetic transformation of Drosophila with transposable elementvectors. Science 218, 348–353
    OpenUrlCrossRefPubMedWeb of Science
    1. Rushlow C. A.,
    2. Han K.,
    3. Manley J. L.,
    4. Levine M.
    (1989) The graded distribution of the dorsal morphogen is initiated by selective nuclear transport. Cell 59, 1165–1177
    OpenUrlAbstract/FREE Full Text
    1. Rutledge B. J.,
    2. Zhang K.,
    3. Bier E.,
    4. Jan Y. N.,
    5. Perrimon N.
    (1992) The Drosophila spitz gene encodes a putative EGF-like growth factor involved in dorsal-ventral axis formation and neurogenesis. Genes Dev 6, 1503–1517
    OpenUrlAbstract/FREE Full Text
    1. Schneider D. S.,
    2. Hudson K. L.,
    3. Lin T.-Y.,
    4. Anderson K.V.
    (1991) Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev 5, 797–807
    OpenUrlAbstract
    1. Schneider D. S.,
    2. Jin Y.,
    3. Morisato D.,
    4. Anderson K. V.
    (1994) A processed form of Spätzleprotein defines dorsal-ventral polarity in the Drosophila embryo. Development 120, 1243–1250
    OpenUrlCrossRefPubMedWeb of Science
    1. Shelton C. A.,
    2. Wasserman S. A.
    (1993) pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. Cell 72, 515–525
    1. Shrestha R.,
    2. Gateff E.
    (1982) Ultrastructure and cytochemistry of the cell types in the larval hematopoietic organs and hemolymph of Drosophila melanogaster. Develop. Growth and Differ 24, 65–82
    OpenUrlCrossRefPubMedWeb of Science
    1. Steward R.,
    2. Zusman S. B.,
    3. Huang L. H.,
    4. Schedl P.
    (1988) Thedorsal protein is distributed in a gradient in early Drosophila embryos. Cell 55, 487–495
    OpenUrlCrossRefPubMedWeb of Science
    1. Steward R.
    (1989) Relocalization of the dorsal protein from the cytoplasm to the nucleus correlates with its function. Cell 59, 1179–1188
    OpenUrlAbstract/FREE Full Text
    1. Tatei K.,
    2. Levine M.
    (1995) Specificity of Rel inhibitor interactions in Drosophila embryos. Mol. Cell. Biol 15, 3627–3634
    OpenUrlAbstract/FREE Full Text
    1. Van Antwerp D. J.,
    2. Martin S. J.,
    3. Kafri T.,
    4. Green D. R.,
    5. Verma I.
    (1996) Suppression of TNF--induced apoptosis by NF- B. Science 274, 787–789
    OpenUrlAbstract/FREE Full Text
    1. Wang C.-Y.,
    2. Mayo M. W.,
    3. Baldwin A. S.
    (1996) TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF- B. Science 274, 784–787
    OpenUrlCrossRefPubMedWeb of Science
    1. Watson K. L.,
    2. Johnson T. K.,
    3. Denell R. E.
    (1991) Lethal (1) aberrant immune response mutations leading to melanotic tumor formation in Drosophila melanogaster. Dev. Genet 12, 173–187
    OpenUrlCrossRefPubMedWeb of Science
    1. Weih F.,
    2. Carrasco D.,
    3. Durham S. K.,
    4. Barton D. S.,
    5. Rizzo C. A.,
    6. Ryseck R. P.,
    7. Lira S. R.,
    8. Bravo R.
    (1995) Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-B/Rel family. Cell 80, 331–340
    OpenUrlAbstract/FREE Full Text
    1. Whalen A. M.,
    2. Steward R.
    (1993) Dissociation of the dorsal-cactus complex and phosphorylation of the dorsal protein correlate with the nuclear localization of dorsal. J. Cell Biol 123, 523–534
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JOURNAL ARTICLES
A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis
P. Qiu, P.C. Pan, S. Govind
Development 1998 125: 1909-1920;
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