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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 “gene search vector”, 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
Asc Prof Takaomi Sakai e-mail
Ast Prof Tsunaki Asano e-mail
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, Tsunoda M, Aigaki T, Maruyama N, Ishigami A. (2013) Effect of ascorbic acid deficiency on catecholamine synthesis in adrenal glands of SMP30/GNL knockout mice. Eur J Nutr. In Press.
  2. Trindade LS, Aigaki T, Peixoto AA, Balduino A, Mânica da Cruz IB, Heddle JG. (2013) A novel classification system for evolutionary aging theories. Front Genet. 4:25.
  3. Cheng Z, Tsuda M, Kishita Y, Sato Y, Aigaki T. (2013) Impaired energy metabolism in a Drosophila model of mitochondrial aconitase deficiency. Biochem Biophys Res Commun. 433, 145-150.
  4. Aizawa S, Senda M, Harada A, Maruyama N, Ishida T, Aigaki T, Ishigami A, Senda T. (2013) Structural basis of the γ-lactone-ring formation in ascorbic acid biosynthesis by the senescence marker protein-30/gluconolactonase. PLoS One. 8,e53706.
  5. Kadengodlu PA, Aigaki T, Abe H, Ito Y. (2013) Cationic cholesterol-modified gelatin as an in vitro siRNA delivery vehicle. Mol Biosyst. 9, 965-968.
  6. Tomioka S, Aigaki T, Matsuo T. (2012) Conserved cis-regulatory elements of two odorant-binding protein genes, Obp57d and Obp57e, in Drosophila. Genes Genet Syst. 87, 323-329.
  7. Sakai, T., Sato, S., Ishimoto, H., Kitamoto, T. (2013). Significance of the centrally expressed TRP channel Painless in Drosophila courtship memory. Learning & Memory 20, 34-40.
  8. Asano T., Taoka M., Shinkawa T., Yamauchi Y., Isobe T., Sato D.（2013）Identification of a cuticle protein with unique repeated motifs in the silkworm, Bombyx mori. Insect Biochem. Molec. Biol. 43, 344-351.
  9. Kadengodlu PA, Hebishima T, Takeshima SN, Ito M, Liu M, Abe H, Aida Y, Aigaki T, Ito Y. (2012) Positively charged cholesterol-recombinant human gelatins foster the cellular uptake of proteins and murine immune reactions. J Nanomedicine. 7, 5437-5450.
  10. Amano A, Tsunoda M, Aigaki T, Maruyama N, Ishigami A. (2012) Age-related changes of dopamine, noradrenaline and adrenaline in adrenal glands of mice. Geriatr Gerontol. 13,490-496.
  11. Nakagawa-Yagi Y, Sato Y, Matsumoto E, Nakatsuka SI, Sakaki T, Muramatsu Y, Hara T, Aigaki T. (2012) Pharmacological modulation of histone demethylase activity by a small molecule isolated from subcritical water extracts of Sasa senanensis leaves prolongs the lifespan of Drosophila melanogaster. BMC Complement Altern Med. 12,101.
  12. Trindade LS, Balduino A, Aigaki T, Heddle JG. (2012) Senemorphism: a novel perspective on aging patterns and its implication for diet-related biology. Biogerontology. 13457-13466.
  13. Takeo S, Swanson SK, Nandanan K, Nakai Y, Aigaki T, Washburn MP, Florens L, Hawley RS. (2012) Shaggy/glycogen synthase kinase 3β and phosphorylation of Sarah/regulator of calcineurin are essential for completion of Drosophila female meiosis. Proc Natl Acad Sci U S A, 109,6382-6389
  14. Kishita Y, Tsuda M, Aigaki T. (2012) Impaired fatty acid oxidation in a Drosophila model of mitochondrial trifunctional protein (MTP) deficiency. Biochem Biophys Res Commun. 419, 344-349.
  15. Harada E, Nakagawa J, Asano T, Taoka M, Sorimachi H, Ito Y, Aigaki T, Matsuo T. (2012) Functional evolution of duplicated odorant-binding protein genes, Obp57d and Obp57e, in Drosophila. PLoS One, 7, e29710.
  16. Kourosh Shahpasand, Isao Uemura, Taro Saito, Tsunaki Asano, Kenji Hata, Keitaro Shibata, Yoko Toyoshima, Masato Hasegawa and Shin-ichi Hisanaga,（2012）Regulation of mitochondrial transport and inter-microtubule spacing by Tau phosphorylation at the sites hyperphosphorylated in Alzheimer’s disease, J. Neuroscience, 32, 2430-2441.
  17. Tomita J, Mitsuyoshi M, Ueno T, Aso Y, Tanimoto H, Nakai Y, Aigaki T, Kume S, Kume K. (2011) Pan-neuronal knockdown of calcineurin reduces sleep in the fruit fly, Drosophila melanogaster. J Neurosci. 31, 13137-13146.
  18. Amano A, Handa S, Aigaki T, Shigemoto K, Maruyama N, Ishigami A. (2011) Establishment and characterization of hepatocytes from an Immortomouse/SMP30/GNL knockout mouse hybrid lacking vitamin C to study vitamin C transport. J Biochem. 150, 671-678.
  19. Nakai Y, Horiuchi J, Tsuda M, Takeo S, Akahori S, Matsuo T, Kume K, Aigaki T. (2011) Calcineurin and its regulator sra/DSCR1 are essential for sleep in Drosophila. J Neurosci, 3012759-3012766.
  20. Wang W, Hara S, Liu M, Aigaki T, Shimizu S, Ito Y. (2011) Polypeptide aptamer selection using a stabilized ribosome display. J Biosci Bioeng, 112, 515-517.
  21. Rotkopf S, Hamberg Y, Aigaki T, Snapper SB, Shilo BZ, Schejter ED. (2011) The WASp-based actin polymerization machinery is required in somatic support cells for spermatid maturation and release. Development, 188, 105-125.
  22. Brumby AM, Goulding KR, Schlosser T, Loi S, Galea R, Khoo P, Bolden JE, Aigaki T, Humbert PO, Richardson HE. (2011） Identification of Novel Ras-cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-family/JNK Pathway is a Central Driver of Tumorigenesis. Genetics, 188, 105-125.
  23. Funakoshi M, Tsuda M, Muramatsu K, Hatsuda H, Morishita S, Aigaki T. (2011） A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. Biochem Biophys Res Commun. 405, 667-72.
  24. Tsuda M, Kawaida R, Kobayashi K, Shinagawa A, Sawada T, Yamada R, Yamamoto K, Aigaki T. (2010） POSH promotes cell survival in Drosophila and in human RASF cells. FEBS Lett, 584, 4689-4694.
  25. Sakai T, Aigaki T. (2010） The Drosophila calcineurin regulator, Sarah, is involved in male courtship. Neuroreport. 21, 985-988.
  26. Sakai T, Aigaki T. (2010） Overexpression of a repressor isoform of CrebB-17A lengthens courtship break in the fruit fly Drosophila melanogaster (Diptera: Drosophilidae）. Appl. Entomol. Zool. 45, 533-539.
  27. Ueyama M, Akimoto Y, Ichimiya T, Ueda R, Kawakami H, Aigaki T, Nishihara S. (2010） Increased apoptosis of myoblasts in Drosophila model for the Walker-Warburg syndrome. PLoS One, 5, e11557.
  28. Yasukawa J, Tomioka S, Aigaki T, Matsuo T. (2010） Evolution of expression patterns of two odorant-binding protein genes, Obp57d and Obp57e, in Drosophila. Gene, 467, 25-34.
  29. Yamazaki D, Horiuchi J, Miyashita T, Saitoe M. (2010） Acute inhibition of PKA activity at old ages ameliorates age-related memory impairment in Drosophila. J Neurosci, 30, 15573-15577.
  30. Tsuda M, Ootaka R, Ohkura C, Kishita Y, Seong KH, Matsuo T, Aigaki T. (2010） Loss of Trx-2 enhances oxidative stress-dependent phenotypes in Drosophila. FEBS Lett, 584, 3398-3401.
  31. Takeo S, Hawley RS, Aigaki T. (2010） Calcineurin and its regulation by Sra/RCAN is required for completion of meiosis in Drosophila. Dev Biol, 344, 957-967.
  32. Tsuda M, Kobayashi T, Matsuo T, Aigaki T. (2010） Insulin-degrading enzyme antagonizes insulin-dependent tissue growth and Abeta-induced neurotoxicity in Drosophila. FEBS Lett, 584, 2916-2920.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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)
  39. 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.
  40. 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.
  41. Matsuo, T. (2008) Rapid evolution of two odorant-binding protein genes, Obp57d and Obp57e, in the Drosophila melanogaster species group. Genetics 178:1061-1072.
  42. 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.
  43. Matsuo, T. (2008) Genes for host-plant selection in Drosophila. J. Neurogenetics 22:195-210
  44. 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.
  45. 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.
  46. 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, 146,19-28.
  47. 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.
  48. 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.
  49. 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
  50. 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. 207-217.
  51. 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
  52. 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. 2, .606-610.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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
  58. 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. 282, 11180-11187.
  59. 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. 64,157-163.
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