TOKYO METROPOLITAN UNIVERSITY
Department of Biological Sciences
Laboratories
Molecular Neuroscience
Neurobiology
Developmental Programs
Cellular Genetics
Molecular Genetics
Plant Hormone Mechanism
Cellular Biochemistry
Stemcell Regeneration
Evolutionary Genetics
Plant Photoregulation
Cell Energetics
Environmental Microbiology
Animal Ecology
Plant Ecology
Systematic Zoology
Systematic Botany
Photo Cellular Genetics Laboratory
We are interested in the structure and function of the Drosophila melanogaster genome. Genetic approaches in this model organism have defined many genes that have been informative for understanding the function of their counterparts in vertebrates including humans. However, not all genes show phenotypic changes when mutated: the phenotype may be too subtle to be detected, or other genes may compensate for the defects. It is estimated that approximately two-thirds of genes belong to this category. To overcome this limitation, we conducted a large-scale insertional mutagenesis using a series of P-element based ggene search vectorh, which, when inserted in the genome, allows GAL4-dependent misexpression of the vector-flanking genes. We generated approximately 16,000 lines carrying a GS vector, of which 12,000 have been mapped on the genome. The collection provides opportunities to identify novel genes based on the misexpression phenotypes, which can be induced tissue- or stage-specifically depending on the GAL4 drivers to be used. We are working on different classes of phenotypes, such as longevity or behavior that have not been fully explored. Some of the on-going projects are described below.
Faculty
Prof
Toshiro Aigaki
e-mail
aigaki-toshiro@tmu.ac.jp
Asc Prof
Takaomi Sakai
e-mail
sakai-takaomi@center.tmu.ac.jp
Asc Prof
Junjiro Horiuchi
e-mail
horiuchi@tmu.ac.jp
Ast Prof
Takashi Matsuo
e-mail
mts@tmu.ac.jp
Ast Prof
Tsunaki Asano
e-mail
asano-tsunaki@tmu.ac.jp
Longevity genes
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We screened for genes whose misexpression extends adult longevity using the collection of GS lines and a heatshock promoter-GAL4 transgene to induce misexpression in a temperature-dependent manner. The screen identified Posh, which encodes a protein with a RING finger and four SH3 domains. We found that overexpression of POSH activates the JNK pathway, which is known to extend longevity. On the other hand, flies deleted for POSH become more susceptible to infection by E. coli, which activates the innate immune system. The mutant flies activate the pathway upon infection but more slowly than in wild-type flies, and fail to turn it off at the proper timing, indicating that POSH is required for proper activation and termination of the innate immune system.
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Behavior genes
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With respect to genes related to behavior, we focused on the female sexual behavior. Wild-type virgin females are receptive to courting males, whereas mated females reject males and lay many eggs. Using the collection of GS lines and neural-specific GAL4 transgene, we searched for genes whose misexpression in the nervous system results in virgin females who behave like mated ones. We identified sra, a homolog of human Down syndrome critical region 1 (DSCR1) or Modulatory calcineurin-interacting protein (MCIP). Virgin females misexpressing sra show a high level of spontaneous ovulation and reject males as mated females. sra is expressed predominantly in neurons and during oogenesis. In accordance with the expression pattern, loss-of-function mutants are behaviorally abnormal, and female sterile with defective meiosis. We showed that the expression level of sra is critical for proper control of behavior, ovulation and female meiosis.
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Regulation of gene expression in complex loci
We are studying the structure and function of lola, one of the most complex loci in the Drosophila genome. The gene contains at least 32 exons and produces at least 80 mRNA isoforms encoding 20 protein isoforms, each of which consists of an N-terminal constant region with BTB domain and C-terminal variable region containing a Zn-finger motif. A unique feature of the lola gene is mRNA processing by trans-splicing: the transcripts containing the constant region are joined to an independently transcribed pre-mRNA encoding a variable region. We are investigating how the mRNA processing is regulated, and how the functions of isoforms are differentiated from each other.
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Learning and memory in Drosophila
What are the molecular pathways that are required for learning and memory? We are studying this question by measuring memory in wild-type and mutant Drosophila and looking for differences in memory retention. Thus far, we have determined that mutations in a gene encoding a protein kinase, cAMP-dependent protein kinase (PKA), significantly improve memory in flies. These are the first single point mutations identified in any species that improve memory and we are very interested in knowing how they function.
Recent Publications
  1. Amano A, Aigaki T, Maruyama N, Ishigami A. (2010) Ascorbic acid depletion enhances expression of the sodium-dependent vitamin C transporters, SVCT1 and SVCT2, and uptake of ascorbic acid in livers of SMP30/GNL knockout mice. Arch Biochem Biophys. 496, 38–44.
  2. Ahsan, B., Saito, TL., Hashimoto, S., Muramatsu, K., Tsuda, M., Sasaki, A., Matsushima, K., Aigaki, T. and Morishita, S. (2009) MachiBase: a Drosophila melanogaster 5'-end mRNA transcription database. Nucleic Acids Res. 37, D49-53.
  3. Tsubouchi, A., Tsuyama, T., Fujioka, M., Kohda, H., Okamoto-Furuta, K., Aigaki, T. and Uemura, T. (2009) Mitochondrial Protein Preli-like Is Required for Development of Dendritic Arbors and Prevents Their Regression in the Drosophila Sensory Nervous System. Development, 136, 3757-3766.
  4. Sakai T, Kasuya J, Kitamoto T, Aigaki T. (2009) The Drosophila TRPA channel, Painless, regulates sexual receptivity in virgin females. Genes Brain Behav. 8, 546-557
  5. Suzuki, E., Zhao Y., Ito, S., Sawatsubashi, S., Murata, T., Furutani, T., Shirode, Y., Yamagata, K., Tanabe, M., Kimura, S., Ueda, T., Fujiyama, S., Lim, J., Matsukawa, H., Kouzmenko, AP., Aigaki, T., Tabata, T., Takeyama, KI, and Kato, S. (2009) Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity. Proc Natl Acad Sci USA. 106, 3818-3822.
  6. Olivier L, Togawa T, Tsuda M, Matsuo T, Loic E and Aigaki T., Overexpression of grappa encoding a histone methyltransferase enhances stress resistance in Drosophila, Hereditas 146, 19-28. (2009)
  7. Jun Yatsu, Tsunaki Asano (2009) Cuticle laccase of the silkworm, Bombyx mori: Purification, gene identification and presence of its inactive precursor in the cuticle. Insect Biochem and Mol Biol 39(4), 254-262
  8. H. Ishimoto, T. Sakai, and T. Kitamoto (2009) Ecdysone signaling regulates courtship long-term memory formation in adult Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 106: 6376-6381.
  9. Matsuo, T. (2008) Rapid evolution of two odorant-binding protein genes, Obp57d and Obp57e, in the Drosophila melanogaster species group. Genetics 178:1061-1072
  10. Harada, E., Haba, D., Aigaki, T., Matsuo, T. (2008) Behavioral analyses of mutants for two odorant-binding protein genes, Obp57d and Obp57e, in Drosophila melanogaster. Genes Genet. Syst. 83:257-264
  11. Matsuo, T. (2008) Genes for host-plant selection in Drosophila. J. Neurogenetics 22:195-210
  12. Matsuno M, Horiuchi J, Tully T, Saitoe M. (2008) The Drosophila cell adhesion molecule klingon is required for long-term memory formation and is regulated by Notch. Proc Natl Acad Sci USA. 106, 310-315
  13. Horiuchi, J., Yamazaki, D., Naganos, S., Aigaki, T. and Saitoe, M. (2008) Protein kinase A inhibits a consolidated form of memory in Drosophila. Proc Natl Acad Sci USA. 105, 20976-20981.
  14. List, O., Togawa, T., Tsuda, M., Matsuo, T., Elard, L. and Aigaki, T. (2009) Overexpression of grappa encoding a histone methyltransferase enhances stress resistance in Drosophila. Hereditas, in press.
  15. Suzuki, E., Zhao Y., Ito, S., Sawatsubashi, S., Murata, T., Furutani, T., Shirode, Y., Yamagata, K., Tanabe, M., Kimura, S., Ueda, T., Fujiyama, S., Lim, J., Matsukawa, H., Kouzmenko, AP., Aigaki, T., Tabata, T., Takeyama, KI, and Kato, S. (2009) Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity. Proc Natl Acad Sci USA.106, 3818-3822.
  16. Ahsan, B., Saito, TL., Hashimoto, S., Muramatsu, K., Tsuda, M., Sasaki, A., Matsushima, K., Aigaki, T. and Morishita, S. (2009) MachiBase: a Drosophila melanogaster 5'-end mRNA transcription database. Nucleic Acids Res. 37, D49-53.
  17. Shindo, M., Wada, H., Kaido, M., Tateno, M., Aigaki, T., Tsuda, L. and Hayashi, S. (2008) Dual function of Src in the maintenance of adherens junctions during tracheal epithelial morphogenesis. Development 135, 1355-1364
  18. Kaji, K., Tomino, S., and Asano, T. (2009) A serine protease in the midgut of the silkworm, Bombyx mori: Protein sequencing, identification of cDNA, demonstration of its synthesis as zymogen form and activation during midgut remodeling. Insect Biochem and Mol biol. 39. 207-17.
  19. Asano, T. and Takebuchi, K. (2009) Identification of the gene encoding pro-phenoloxidase A3 in the fruitfly, Drosophila melanogaster. Insect Mol Biol. 18, 223-232
  20. Nam, H-J. Jang, I-H., Asano, T. and Lee, W-J. (2008) Involvement of pro-phenoloxidase 3 in lamellocyte-meidated spontaneous melanization in Drosophila. Molecular and Cells. 2008. 2, .606-610
  21. Yao, Y., Wu, Y., Yin, C., Ozawa, R., Aigaki, T., Wouda, R.R., Noordermeer, J.N., Fradkin, L.G., Hing, H. (2007) Antagonistic roles of Wnt5 and the Drl receptor in patterning the Drosophila antennal lobe. Nat Neurosci. 10, 1423-1432
  22. Taniguchi K, Hozumi S, Maeda R, Ooike M, Sasamura T, Aigaki T, Matsuno K. (2007) D-JNK signaling in visceral muscle cells controls the laterality of the Drosophila gut. Dev Biol. 311, 251-263
  23. Tsuda M, Sugiura T, Ishii T, Ishii N, Aigaki T. (2007) A mev-1-like dominant-negative SdhC increases oxidative stress and reduces lifespan in Drosophila. Biochem Biophys Res Commun. 363, 342-346.
  24. Sakurai T, K., Kojima, T., Aigaki, T., *Hayashi, S (2007) Differential control of cell affinity required for progression and refinement of cell boundary during Drosophila leg segmentation, Dev Biol, 309, 126-136
  25. Matsuo, T., Sugaya, S., Yasukawa, J., Aigaki, T., Fuyama, Y. (2007) Odorant-Binding Proteins, OBP57d and OBP57e, Affect Taste Perception and Host-Plant Preference in Drosophila sechellia. PLoS Biology. 5(5): e118
  26. Umeda-Kameyama, Y., Tsuda, M., Ohkura, C., Matsuo, T., Namba, Y., Ohuchi, Y. and Aigaki, T. (2007) Thioredoxin suppresses Pael-R-induced neurotoxicity and extends longevity in Drosophila. J. Biol. Chem. In press
  27. Shima, S., Aigaki, T., Nojima, T. and Yamamoto, D. (2007) Identification of trf2 mutants of Drosophila with defects in anterior spiracle eversion. Arch. Insect Biochem. Physiol. In press
  28. Peyre, J-B., Seabrooke, S., Randlett, O., Kisiel, M., Aigaki, T., Stewart, B.A. (2006) Interaction of cytoskeleton genes with Drosophila NSF2 neuromuscular junction overgrowth. Genesis 44, 595-600
  29. Villella, A., Peyre, J-B., Aigaki T. and Hall, J.C. (2006) Defective transfer of seminal-fluid materials during matings of semi-fertile fruitless mutants in Drosophila. J Comp Physiol A: Neuroethol Sens, Neural Behav Physiol. 192, 1253-1269.
  30. Oshima, K., Takeda, M., Kuranaga, E., Ueda, R., Aigaki, T., Miura, M. and Hayashi, S. (2006) IKKe regulates F-actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis. Curr. Biol. 16, 1531-1537
  31. Takeo, S., Tsuda, M., Akahori, S., Matsuo, T. and Aigaki, T. (2006) The calcineurin regulator Sra plays an essential role in female meiosis in Drosophila. Curr. Biol. 16, 1435-1440
  32. Tsuda, L., Kaido, M., Lim,Y.M., Kato, K., Aigaki, T., and Hayashi, S. (2006) An NRSF/REST-like repressor under negative control of Su(H)/SMRTER/Ebi repressor complex regulates eye development in Drosophila. EMBO J. 25, 3191-3202
  33. Tsuda, M., Seong K.-H. and Aigaki, T. (2006) POSH, a scaffold protein for JNK signaling, binds to ALG-2 and ALIX in Drosophila. FEBS lett. 580, 3296-300
  34. Zhang, D., Zhou, W., Yin, C., Chen, W., Ozawa, R., Ang, L.H., Anandan, L., Aigaki, T. and Hing, H. (2006) Misexpression screen for genes altering the olfactory map in Drosophila. Genesis 44, 189-201
  35. Hozumi, S., Maeda, R., Taniguchi, K., Kanai, M., Shirakabe, S., Sasamura, T., Speder, P., Noselli, S., Aigaki, T., Murakami, R. and Matsuno, K. (2006) An unconventional myosin in Drosophila reverses the default handedness in visceral organs. Nature 440, 798-802
  36. Sakai, T. and Kitamoto, T. (2006) Clock, love and memory: Circadian and non-circadian regulation of Drosophila mating behavior by clock genes. Sleep and Biol. Rhythms. 4, 255-262
  37. Sakai, T. and Kitamoto, T. (2006) Differential roles of two major brain structures, mushroom bodies and central complex, for Drosophila male courtship behavior. J. Neurobiol. 66, 821-834
  38. Horiuchi, T. and Aigaki, T. (2006) Alternative trans-splicing: a novel mode of pre-mRNA processing. Biol. Cell, 98, 135-140
  39. Katsuyama, T., Sugawara, T., Tatsumi, M., Oshima, Y., Gehring, W., Aigaki, T. and Kurata, S. (2005) Involvement of winged eye encoding a chromatin-associated bromo-adjacent homology domain protein in disc specification. Proc. Natl. Acad. Sci. USA, 102, 15918-15923
  40. Kanuka, H, Hiratou, T, Igaki, T, Kanda, H, Kuranaga, E, Sawamoto, K, Aigaki, T, Okano, H, and Miura, M. (2005) Gain-of-function screen identifies a role of the Sec61alpha translocon in Drosophila postmitotic neurotoxicity. Biochim. Biophys. Acta 1726, 225-237
  41. Tsuda, M., Langmann, C., Harden, N. and Aigaki, T. (2005) The RING finger-scaffold protein POSH targets TAK1 to control immunity signaling in Drosophila. EMBOr 6, 1082-1087
  42. Takeo, S., Akiyama, T., Firkus, C., Aigaki, T. and Nakato, H. (2005) Expression of a secreted form of Dally, a Drosophila glypican, induces overgrowth phenotype by affecting action range of Hedgehog. Dev. Biol. 284, 204 - 218
  43. Laviolette, M.J., Nunes, N., Peyre , J.B., Aigaki, T. and Stewart, B. A. (2005) A Genetic Screen for Suppressors of Drosophila NSF2 Neuromuscular Junction Overgrowth. Genetics 170, 779-792
  44. Orihara-Ono, M., Suzuki, M., Saito, M., Yoda, Y., Aigaki,T. and Hama, C. (2005) The slender lobes gene, identified by retarded mushroom body development, is required for proper nucleolar organization in Drosophila. Dev. Biol. 281, 121-133
  45. Kotani, N.,@Kitazume, S., Kamimura, K., Takeo, S., Aigaki,T., Nakato, H. and Hashimoto, Y. (2005). Drosophila orthologues of human b-secretase induce the secretion of a Golgi-resident transferase, heparan sulfate 6-O-sulfotransferase. J. Biochem. 137, 315-22.
  46. Kawahara, Y., Matsuo, T., Nozawa, M., Shin-I, T., Kohara, Y. and Aigaki, T. (2004) Comparative sequences analysis of a gene-dense region among closely related species of Drosophila melanogaster. Gen Genet. Sys. 79, 351-359
  47. Sakata, T., Sakaguchi, H., Tsuda, L., Higashitani, A., Aigaki, T., Matsuno, K. and Hayashi, S. (2004) Drosophila Nedd4 regulates endocytosis of Notch and suppresses its ligand-independent activation. Curr. Biol. 14, 2228-2236
  48. Ejima, A., Tsuda, M., Takeo, S., Ishii, K., Matsuo, T. and Aigaki, T. (2004) Expression level of sarah, a homolog of DSCR1 is critical for ovulation and female courtship behavior in Drosophila melanogaster. Genetics 168, 2077-2087
  49. Tanaka, H., Takasu, E., Aigaki, T., Kato, K., Hayashi, S. and Nose, A. (2004) Formin3 is required for assembly of the F-actin structure that mediates tracheal fusion in Drosophila. Devel. Biol. 274, 413-425
  50. Aigaki, T., Kaneuchi, T., Matsuo, T., Seong, K-H., and Togawa, T. (2004) Genetic Bases of Oxidative Stress Resistance and Life span in Drosophila. J. Clin. Biochem. Nut. 34, 77-83
  51. Takeo S., Fujise, M., Akiyama, T., Habuchi, H., Itano, N., Matsuo, T., Aigaki, T., Kimata, K., and Nakato, H. (2004) In vivo hyaluronan synthesis by expression of mammalian hyaluronan synthase gene in Drosophila. J. Biol. Chem. 279,18920-18925
  52. Horiuchi, T., Giniger, E., and Aigaki, T. (2003) Alternative trans-splicing of constant and variable exons of a Drosophila axon guidance gene, lola. Genes Dev. 17, 2496-2501
  53. Goeke, S., Greene, E.A., Grant, P.K., Gates, M.A., Crowner, D., Aigaki, T. and Giniger, E. (2003) Alternative splicing of lola generates 19 transcription factors controlling axon guidance in Drosophila. Nat. Neurosci. 6, 917-924
  54. Ohsako, T., Horiuchi, T., Matsuo, T., Komaya, S. and Aigaki, T. (2003) Drosophila lola encodes a family of BTB-transcription regulators with highly variable C-terminal domains containing zinc finger motifs. Gene 311, 59-69
  55. Kaneuchi, T., Togawa, T., Matsuo, T., Fuyama, Y. and Aigaki, T. (2003) Efficient method for measurement of H2O2 resistance in Drosophila. Biogerontology 4, 157-165
  56. Fujise, M., Takeo, S., Kamimura, K., Matsuo, T., Aigaki, T., Izumi, S. and Nakato, H. (2003) Dally regulates Dpp morphogen gradient formation in the Drosophila wing. Development 130, 1515-1522
  57. Hayashi, S., Ito, K., Sado, Y., Taniguchi, M., Takeuchi, H., Aigaki, T., Matsuzaki, F., Nakagoshi, H., Tanimura, T., Ueda, R., Uemura, T., Yoshihara, M., Goto, S. (2002) GETDB, a database compiling expression patterns and molecular locations of a collection of Gal4 enhancer traps. Genesis, 34, 58-61
  58. Takehana, A., Katsuyama, T., Tamaki, Y., Oshima, Y., Takada, H., Aigaki, T. and Kurata, S. (2002) Overexpression of a pattern-recognition receptor, peptidoglycan-recognition protein-LE, activates imd/relish-mediated antibacterial defense and prophenoloxidase cascade in Drosophila larvae. Proc. Natl. Acad. Sci., 99, 13705-13710
  59. Aigaki, T., Seong, K.H., Matsuo, T. (2002) Longevity determination genes in Drosophila melanogaster. Mech.Age.Dev. 123, 1531-1541.
  60. Igaki, T., Kanda, H., Goto, Y., Kanuka, H., Kuranaga, E. Aigaki, T. and Miura, M. (2002) Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 21, 3009-3018
  61. Umemiya, T., Takasu, E., Takeichi, M., Aigaki, T. and Nose, A. (2002) Forked end: a novel transmembrane protein involved in neuromuscular specificity in Drosophila identified by gain-of-function screening. J. Neurobiol., 51, 205-214
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