Details of the Researcher

PHOTO

Naoyuki Fuse
Section
Graduate School of Pharmaceutical Sciences
Job title
Assistant Professor
Degree

  • Ph.D. (The Graduate University for Advanced Studies)

e-Rad No.
80321983
Profile

I previously studied signal transduction during development. Currently, I am studying innate immunity and environmental adaptation in Drosophila. I am interested in complex biological phenomena, and aim to take a research approach that ‘sees both the forest and the trees’—gaining an overview using omics whilst delving into the molecular level through genetics.

Research History 11

  • 2016/04 - Present
    Tohoku University　Graduate School of Pharmaceutical Sciences　Assistant Professor

  • 2015/04 - 2016/03
    Kyoto University　Graduate School of Biostudies　Researcher

  • 2013/06 - 2015/03
    RIKEN　Center for Developmental Biology　Researcher

  • 2012/04 - 2013/05
    Kyoto University　Graduate School of Science Division of Biological Sciences　Researcher

  • 2008/06 - 2012/03
    Kyoto University　Graduate School of Science Division of Biological Sciences　GCOE Researcher

  • 2004/06 - 2008/05
    National Institute of Genetics　Assistant Professor

  • 2002/04 - 2004/05
    RIKEN　Center for Developmental Biology　Researcher

  • 1999/10 - 2002/03
    Tohoku University　Institute of Development, Aging and Cancer　Assistant Professor

  • 1995/09 - 1999/09
    Johns Hopkins University　School of Medicine, Department of Molecular Biology & Genetics　Postdoctoral Fellow

  • 1995/04 - 1995/08
    National Institute of Genetics

  • 1990/04 - 1992/03
    新日本製鐵（株）　先端技術研究所　社員

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Education 3

  • The Graduate University for Advanced Studies　School of Life Science　Department of Genetics

    1992/04 - 1995/03

  • Sophia University　Graduate School of Science and Technology　Master's(Doctoral) Program in Chemistry

    1988/04 - 1990/03

  • Sophia University　Faculty of Science and Technology　Department of Chemistry

    1984/04 - 1988/03

Research Interests 9

  • evolution

  • morphogenesis

  • innate immunity

  • environmental adaptation

  • genome

  • 包括脳ネットワーク

  • neural stem cell

  • G protein

  • Drosophila

Research Areas 4

  • Life sciences / Genetics /

  • Life sciences / Animals: biochemistry, physiology, behavioral science /

  • Life sciences / Developmental biology /

  • Life sciences / Genomics /

Papers 34

  1. Regulation of Gut Starvation Responses Through Drosophila<scp>NP3253</scp> Neurons

    Quang‐Dat Nguyen, Kiho Fujii, Kentaro Ishibashi, Haruka Hashiba, Wakako Ohtsubo, Haruki Kitazawa, Hiromu Tanimoto, Naoyuki Fuse, Shoichiro Kurata

    Genes to Cells　30　(2)　2025/02/04

    Publisher: Wiley

    DOI： 10.1111/gtc.70005 　

    ISSN： 1356-9597

    eISSN： 1365-2443

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    ABSTRACT The “gut–brain axis,” a bidirectional communication system between the gastrointestinal tract and the central nervous system, plays a crucial role in regulating complex physiological functions in response to nutrients, pathogens, and microbiota. However, the cellular and molecular mechanisms governing this regulation remain poorly understood. Using Drosophila melanogaster as a model organism, we previously identified NP3253 neurons, located in both the brain and gut, as key contributors to gut homeostasis during oral bacterial infection. Here, we found a novel role of NP3253 neurons in regulating starvation resistance. We observed that a subset of NP3253 neurons in the gut were activated during starvation. To investigate downstream effect, we conducted RNA‐Seq analysis on the gut of adult flies with genetically silenced NP3253 neurons, comparing gene expression under starved and fed conditions. This analysis identified 26 genes differentially expressed in response to both starvation and NP3253 neuronal activity. Among these, CG12643, encoding an uncharacterized short peptide, was found to be essential for starvation resistance in the gut. Our findings demonstrate that NP3253 neurons modulate the gut gene expression in response to starvation, thereby supporting physiological adaptation to environmental stressors.

  2. Gut microbiota–mediated lipid accumulation as a driver of evolutionary adaptation to blue light toxicity in Drosophila

    Yuta Takada, Toshiharu Ichinose, Naoyuki Fuse, Kokoro Saito, Wakako Ikeda-Ohtsubo, Hiromu Tanimoto, Masatoshi Hori

    Communications Biology　2024/08/23

    DOI： 10.1101/2024.08.22.608892 　

  3. Blue light toxicity drives the gut microbiota-mediated lipid accumulation in Drosophila

    Yuta Takada, Toshiharu Ichinose, Naoyuki Fuse, Kokoro Saito, Wakako Ikeda-Ohtsubo, Hiromu Tanimoto, Masatoshi Hori

    2024/08/23

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2024.08.22.608892 　

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    Blue light (BL), abundant in sunlight, is highly toxic to many insect species when exposure is excessive. While the physiological mechanisms of BL toxicity are being revealed, the evolutionary responses remain less explored. In this study, using Drosophila melanogaster as a model system, we conducted laboratory selection for over 60 generations under excessive BL exposure. The selected line (SL) flies exhibited enhanced BL-tolerance, and also increased body weight and lipid accumulation. Interestingly, we found elongated midgut in the SL flies, and increased microbiota, which was dominated by Acetobacter persici. The BL-tolerance and the lipid accumulation were dependent on the increment of gut microbiota. Genomic analysis identified mutations in the Hippo signaling pathway linked to midgut elongation, while transcriptome analysis showed downregulation of Tachykinin (Tk), a key suppressor of intestinal lipogenesis. Genetically induced lipid accumulation through manipulation of Tk or related lipogenic genes was sufficient to confer BL-tolerance. Moreover, our findings indicate that parental BL irradiation, along with accumulated mutations from laboratory selection, played a crucial role in midgut elongation and increased bacterial abundance. These findings reveal evolutionary responses to excessive BL exposure that shape host traits to maximize the benefits provided by gut microbiota.

  4. Neural control of redox response and microbiota-triggered inflammation in Drosophila gut

    Naoyuki Fuse, Haruka Hashiba, Kentaro Ishibashi, Takuro Suzuki, Quang-Dat Nguyen, Kiho Fujii, Wakako Ikeda-Ohtsubo, Haruki Kitazawa, Hiromu Tanimoto, Shoichiro Kurata

    Frontiers in Immunology　14　1268611　2023/10/26

    Publisher: Frontiers Media SA

    DOI： 10.3389/fimmu.2023.1268611 　

    eISSN： 1664-3224

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    Background The neural system plays a critical role in controlling gut immunity, and the gut microbiota contributes to this process. However, the roles and mechanisms of gut-brain-microbiota interactions remain unclear. To address this issue, we employed Drosophila as a model organism. We have previously shown that NP3253 neurons, which are connected to the brain and gut, are essential for resistance to oral bacterial infections. Here, we aimed to investigate the role of NP3253 neurons in the regulation of gut immunity. Methods We performed RNA-seq analysis of the adult Drosophila gut after genetically inactivating the NP3253 neurons. Flies were reared under oral bacterial infection and normal feeding conditions. In addition, we prepared samples under germ-free conditions to evaluate the role of the microbiota in gut gene expression. We knocked down the genes regulated by NP3253 neurons and examined their susceptibility to oral bacterial infections. Results We found that immune-related gene expression was upregulated in NP3253 neuron-inactivated flies compared to the control. However, this upregulation was abolished in axenic flies, suggesting that the immune response was abnormally activated by the microbiota in NP3253 neuron-inactivated flies. In addition, redox-related gene expression was downregulated in NP3253 neuron-inactivated flies, and this downregulation was also observed in axenic flies. Certain redox-related genes were required for resistance to oral bacterial infections, suggesting that NP3253 neurons regulate the redox responses for gut immunity in a microbiota-independent manner. Conclusion These results show that NP3253 neurons regulate the appropriate gene expression patterns in the gut and contribute to maintain homeostasis during oral infections.

  5. Dilp8 and its candidate receptor, Drl, are involved in the transdetermination of the Drosophila imaginal disc

    Kazuya Nemoto, Keita Masuko, Naoyuki Fuse, Shoichiro Kurata

    Genes to Cells　28　(12)　857-867　2023/10/10

    Publisher: Wiley

    DOI： 10.1111/gtc.13072 　

    ISSN： 1356-9597

    eISSN： 1365-2443

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    Abstract Drosophila imaginal disc cells can change their identity under stress conditions through transdetermination (TD). Research on TD can help elucidate the in vivo process of cell fate conversion. We previously showed that the overexpression of winged eye (wge) induces eye‐to‐wing TD in the eye disc and that an insulin‐like peptide, Dilp8, is then highly expressed in the disc. Although Dilp8 is known to mediate systemic developmental delay via the Lgr3 receptor, its role in TD remains unknown. This study showed that Dilp8 is expressed in specific cells that do not express eye or wing fate markers during Wge‐mediated TD and that the loss of Dilp8 impairs the process of eye‐to‐wing transition. Thus, Dilp8 plays a pivotal role in the cell fate conversion under wge overexpression. Furthermore, we found that instead of Lgr3, another candidate receptor, Drl, is involved in Wge‐mediated TD and acts locally in the eye disc cells. We propose a model in which Dilp8–Drl signaling organizes cell fate conversion in the imaginal disc during TD.

  6. Transcriptome features of innate immune memory in Drosophila

    Naoyuki Fuse, Chisaki Okamori, Ryoma Okaji, Chang Tang, Kikuko Hirai, Shoichiro Kurata

    PLOS Genetics　18　(10)　e1010005-e1010005　2022/10/17

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pgen.1010005 　

    eISSN： 1553-7404

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    Immune memory is the ability of organisms to elicit potentiated immune responses at secondary infection. Current studies have revealed that similar to adaptive immunity, innate immunity exhibits memory characteristics (called "innate immune memory"). Although epigenetic reprogramming plays an important role in innate immune memory, the underlying mechanisms have not been elucidated, especially at the individual level. Here, we established experimental systems for detecting innate immune memory in Drosophila melanogaster. Training infection with low-pathogenic bacteria enhanced the survival rate of the flies at subsequent challenge infection with high-pathogenic bacteria. Among low-pathogenic bacteria, Micrococcus luteus (Ml) and Salmonella typhimurium (St) exerted apparent training effects in the fly but exhibited different mechanisms of action. Ml exerted training effects even after its clearance from flies, while live St persisted in the flies for a prolonged duration. RNA sequencing (RNA-Seq) analysis revealed that Ml training enhanced the expression of the immune-related genes under the challenge condition but not under the non-challenge condition. In contrast, St training upregulated the expression of the immune-related genes independent of challenge. These results suggest that training effects with Ml and St are due to memory and persistence of immune responses, respectively. Furthermore, we searched for the gene involved in immune memory, and identified a candidate gene, Ada2b, which encodes a component of the histone modification complex. The Ada2b mutant suppressed Ml training effects on survival and disrupted the expression of some genes under the training + challenge condition. These results suggest that the gene expression regulated by Ada2b may contribute to innate immune memory in Drosophila.

  7. Genetic dissection of innate immune memory in Drosophila melanogaster

    Chang Tang, Shoichiro Kurata, Naoyuki Fuse

    Frontiers in Immunology　13　2022/08/04

    Publisher: Frontiers Media SA

    DOI： 10.3389/fimmu.2022.857707 　

    eISSN： 1664-3224

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    Current studies have demonstrated that innate immunity possesses memory characteristics. Although the molecular mechanisms underlying innate immune memory have been addressed by numerous studies, genetic variations in innate immune memory and the associated genes remain unclear. Here, we explored innate immune memory in 163 lines of Drosophila melanogaster from the Drosophila Synthetic Population Resource. In our assay system, prior training with low pathogenic bacteria (Micrococcus luteus) increased the survival rate of flies after subsequent challenge with highly pathogenic bacteria (Staphylococcus aureus). This positive training effect was observed in most lines, but some lines exhibited negative training effects. Survival rates under training and control conditions were poorly correlated, suggesting that distinct genetic factors regulate training effects and normal immune responses. Subsequent quantitative trait loci analysis suggested that four loci containing 80 genes may be involved in regulating innate immune memory. Among them, Adgf-A, which encodes an extracellular adenosine deaminase-related growth factor, was shown to be associated with training effects. Our study findings help to elucidate the genetic architecture of innate immune memory in Drosophila and may provide insight for new therapeutic treatments aimed at boosting immunity.

  8. cGMP signaling pathway that modulates NF-κB activation in innate immune responses

    Hirotaka Kanoh, Shinzo Iwashita, Takayuki Kuraishi, Akira Goto, Naoyuki Fuse, Haruna Ueno, Mariko Nimura, Tomohito Oyama, Chang Tang, Ryo Watanabe, Aki Hori, Yoshiki Momiuchi, Hiroki Ishikawa, Hiroaki Suzuki, Kumiko Nabe, Takeshi Takagaki, Masataka Fukuzaki, Li-Li Tong, Sinya Yamada, Yoshiteru Oshima, Toshiro Aigaki, Julian A.T. Dow, Shireen-Anne Davies, Shoichiro Kurata

    iScience　24　(12)　103473-103473　2021/12

    Publisher: Elsevier BV

    DOI： 10.1016/j.isci.2021.103473 　

    ISSN： 2589-0042

  9. A Receptor Guanylate Cyclase, Gyc76C, Mediates Humoral, and Cellular Responses in Distinct Ways in Drosophila Immunity. International-journal Peer-reviewed

    Shinzo Iwashita, Hiroaki Suzuki, Akira Goto, Tomohito Oyama, Hirotaka Kanoh, Takayuki Kuraishi, Naoyuki Fuse, Tamaki Yano, Yoshiteru Oshima, Julian A T Dow, Shireen-Anne Davies, Shoichiro Kurata

    Frontiers in immunology　11　35-35　2020

    DOI： 10.3389/fimmu.2020.00035 　

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    Innate immunity is an evolutionarily conserved host defense system against infections. The fruit fly Drosophila relies solely on innate immunity for infection defense, and the conservation of innate immunity makes Drosophila an ideal model for understanding the principles of innate immunity, which comprises both humoral and cellular responses. The mechanisms underlying the coordination of humoral and cellular responses, however, has remained unclear. Previously, we identified Gyc76C, a receptor-type guanylate cyclase that produces cyclic guanosine monophosphate (cGMP), as an immune receptor in Drosophila. Gyc76C mediates the induction of antimicrobial peptides for humoral responses by a novel cGMP pathway including a membrane-localized cGMP-dependent protein kinase, DG2, through downstream components of the Toll receptor such as dMyD88. Here we show that Gyc76C is also required for the proliferation of blood cells (hemocytes) for cellular responses to bacterial infections. In contrast to Gyc76C-dependent antimicrobial peptide induction, Gyc76C-dependent hemocyte proliferation is meditated by a small GTPase, Ras85D, and not by DG2 or dMyD88, indicating that Gyc76C mediates the cellular and humoral immune responses in distinct ways.

  10. HSP70/DNAJA3 chaperone/cochaperone regulates NF-κB activity in immune responses Peer-reviewed

    Kumada, K., Fuse, N., Tamura, T., Okamori, C., Kurata, S.

    Biochemical and Biophysical Research Communications　513　(4)　947-951　2019

    DOI： 10.1016/j.bbrc.2019.04.077 　

  11. Nuclear Lamin is required for Winged Eye-mediated transdetermination of Drosophila imaginal disc Peer-reviewed

    Masuko, K., Furuhashi, H., Komaba, K., Numao, E., Nakajima, R., Fuse, N., Kurata, S.

    Genes to Cells　23　(8)　724-731　2018/07

    DOI： 10.1111/gtc.12608 　

    ISSN： 1356-9597

  12. winged eye Induces Transdetermination of Drosophila Imaginal Disc by Acting in Concert with a Histone Methyltransferase, Su(var)3-9 Peer-reviewed

    Keita Masuko, Naoyuki Fuse, Kanae Komaba, Tomonori Katsuyama, Rumi Nakajima, Hirofumi Furuhashi, Shoichiro Kurata

    Cell Reports　22　(1)　206-217　2018/01/02

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.celrep.2017.11.105 　

    ISSN： 2211-1247

  13. Jak1/Stat3 signaling acts as a positive regulator of pluripotency in chicken pre-gastrula embryos Peer-reviewed

    Shota Nakanoh, Naoyuki Fuse, Ryosuke Tadokoro, Yoshiko Takahashi, Kiyokazu Agata

    DEVELOPMENTAL BIOLOGY　421　(1)　43-51　2017/01

    DOI： 10.1016/j.ydbio.2016.11.001 　

    ISSN： 0012-1606

    eISSN： 1095-564X

  14. Dynamics of Dark-Fly Genome Under Environmental Selections Peer-reviewed

    Minako Izutsu, Atsushi Toyoda, Asao Fujiyama, Kiyokazu Agata, Naoyuki Fuse

    G3-GENES GENOMES GENETICS　6　(2)　365-376　2016/02

    DOI： 10.1534/g3.115.023549 　

    ISSN： 2160-1836

  15. Verification of chicken Nanog as an epiblast marker and identification of chicken PouV as Pou5f3 by newly raised antibodies Peer-reviewed

    Shota Nakanoh, Naoyuki Fuse, Yoshiko Takahashi, Kiyokazu Agata

    DEVELOPMENT GROWTH & DIFFERENTIATION　57　(3)　251-263　2015/04

    DOI： 10.1111/dgd.12205 　

    ISSN： 0012-1592

    eISSN： 1440-169X

  16. A Novel Cell Death Gene Acts to Repair Patterning Defects in Drosophila melanogaster Peer-reviewed

    Kentaro M. Tanaka, Aya Takahashi, Naoyuki Fuse, Toshiyuki Takano-Shimizu-Kouno

    GENETICS　197　(2)　739-U502　2014/06

    DOI： 10.1534/genetics.114.163337 　

    ISSN： 0016-6731

    eISSN： 1943-2631

  17. Gprk2 adjusts Fog signaling to organize cell movements in Drosophila gastrulation Peer-reviewed

    Naoyuki Fuse, Fengwei Yu, Susumu Hirose

    DEVELOPMENT　140　(20)　4246-4255　2013/10

    DOI： 10.1242/dev.093625 　

    ISSN： 0950-1991

  18. Heterotrimeric G protein signaling governs the cortical stability during apical constriction in Drosophila gastrulation Peer-reviewed

    Takuma Kanesaki, Susumu Hirose, Joerg Grosshans, Naoyuki Fuse

    MECHANISMS OF DEVELOPMENT　130　(2-3)　132-142　2013/02

    DOI： 10.1016/j.mod.2012.10.001 　

    ISSN： 0925-4773

  19. Genome Features of "Dark-Fly", a Drosophila Line Reared Long-Term in a Dark Environment Peer-reviewed

    Minako Izutsu, Jun Zhou, Yuzo Sugiyama, Osamu Nishimura, Tomoyuki Aizu, Atsushi Toyoda, Asao Fujiyama, Kiyokazu Agata, Naoyuki Fuse

    PLOS ONE　7　(3)　e33288　2012/03

    DOI： 10.1371/journal.pone.0033288 　

    ISSN： 1932-6203

  20. Experience-dependent Plasticity of the Optomotor Response in Drosophila melanogaster Peer-reviewed

    Akiko Kikuchi, Shumpei Ohashi, Naoyuki Fuse, Toshiaki Ohta, Marina Suzuki, Yoshinori Suzuki, Tomoyo Fujita, Takuya Miyamoto, Toru Aonishi, Hiroyoshi Miyakawa, Takako Morimoto

    DEVELOPMENTAL NEUROSCIENCE　34　(6)　533-542　2012

    DOI： 10.1159/000346266 　

    ISSN： 0378-5866

    eISSN： 1421-9859

  21. Progenitor properties of symmetrically dividing Drosophila neuroblasts during embryonic and larval development Peer-reviewed

    Atsushi Kitajima, Naoyuki Fuse, Takako Isshiki, Fumio Matsuzaki

    DEVELOPMENTAL BIOLOGY　347　(1)　9-23　2010/11

    DOI： 10.1016/j.ydbio.2010.06.029 　

    ISSN： 0012-1606

  22. Tre1 GPCR initiates germ cell transepithelial migration by regulating Drosophila melanogaster E-cadherin Peer-reviewed

    Prabhat S. Kunwar, Hiroko Sano, Andrew D. Renault, Vitor Barbosa, Naoyuki Fuse, Ruth Lehmann

    JOURNAL OF CELL BIOLOGY　183　(1)　157-168　2008/10

    DOI： 10.1083/jcb.200807049 　

    ISSN： 0021-9525

  23. Evolution of the dorsal-ventral patterning network in the mosquito, Anopheles gambiae Peer-reviewed

    Yury Goltsev, Naoyuki Fuse, Manfred Frasch, Robert P. Zinzen, Gregory Lanzaro, Mike Levine

    DEVELOPMENT　134　(13)　2415-2424　2007/07

    DOI： 10.1242/dev.02863 　

    ISSN： 0950-1991

  24. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly Peer-reviewed

    T Maity, N Fuse, PA Beachy

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　102　(47)　17026-17031　2005/11

    DOI： 10.1073/pnas.0507848102 　

    ISSN： 0027-8424

  25. Differential functions of G protein and Baz-aPKC signaling pathways in Drosophila neuroblast asymmetric division Peer-reviewed

    Y Izumi, N Ohta, A Itoh-Furuya, N Fuse, F Matsuzaki

    JOURNAL OF CELL BIOLOGY　164　(5)　729-738　2004/03

    DOI： 10.1083/jcb.200309162 　

    ISSN： 0021-9525

  26. Heterotrimeric G proteins regulate daughter cell size asymmetry in Drosophila neuroblast divisions Peer-reviewed

    N Fuse, K Hisata, AL Katzen, F Matsuzaki

    CURRENT BIOLOGY　13　(11)　947-954　2003/05

    DOI： 10.1016/S0960-9822(03)00334-8 　

    ISSN： 0960-9822

  27. Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for Patched Peer-reviewed

    N Fuse, T Maiti, BL Wang, JA Porter, TMT Hall, DJ Leahy, PA Beachy

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　96　(20)　10992-10999　1999/09

    DOI： 10.1073/pnas.96.20.10992 　

    ISSN： 0027-8424

  28. Snail-type zinc finger proteins prevent neurogenesis in Scutoid and transgenic animals of Drosophila Peer-reviewed

    Naoyuki Fuse, Hitoshi Matakatsu, Misako Taniguchi, Shigeo Hayashi

    Development Genes and Evolution　209　(10)　573-580　1999

    DOI： 10.1007/s004270050291 　

    ISSN： 0949-944X

  29. Determination of wing cell fate by the escargot and snail genes in Drosophila Peer-reviewed

    N Fuse, S Hirose, S Hayashi

    DEVELOPMENT　122　(4)　1059-1067　1996/04

    ISSN： 0950-1991

  30. DIPLOIDY OF DROSOPHILA IMAGINAL CELLS IS MAINTAINED BY A TRANSCRIPTIONAL REPRESSOR ENCODED BY ESCARGOT Peer-reviewed

    N FUSE, S HIROSE, S HAYASHI

    GENES & DEVELOPMENT　8　(19)　2270-2281　1994/10

    DOI： 10.1101/gad.8.19.2270 　

    ISSN： 0890-9369

  31. PURIFICATION AND CHARACTERIZATION OF NEW ANTI-ADRENOCORTICOTROPIN RABBIT NEUTROPHIL PEPTIDES (DEFENSINS) Peer-reviewed

    N FUSE, Y HAYASHI, J FUKATA, T TOMINAGA, O EBISUI, Y SATOH, T ISOHARA, UNO, I, H IMURA

    EUROPEAN JOURNAL OF BIOCHEMISTRY　216　(2)　653-659　1993/09

    DOI： 10.1111/j.1432-1033.1993.tb18185.x 　

    ISSN： 0014-2956

  32. DISTRIBUTION AND CHARACTERIZATION OF IMMUNOREACTIVE CORTICOSTATIN IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS Peer-reviewed

    T TOMINAGA, J FUKATA, Y HAYASHI, Y SATOH, N FUSE, H SEGAWA, O EBISUI, Y NAKAI, Y OSAMURA, H IMURA

    ENDOCRINOLOGY　130　(3)　1593-1598　1992/03

    DOI： 10.1210/endo.130.3.1537309 　

    ISSN： 0013-7227

  33. STRUCTURE OF THE SNAKE SHORT-CHAIN NEUROTOXIN, ERABUTOXIN-C, PRECURSOR GENE Peer-reviewed

    N FUSE, T TSUCHIYA, Y NONOMURA, A MENEZ, T TAMIYA

    EUROPEAN JOURNAL OF BIOCHEMISTRY　193　(3)　629-633　1990/11

    DOI： 10.1111/j.1432-1033.1990.tb19380.x 　

    ISSN： 0014-2956

  34. SEQUENCE-ANALYSIS OF A CDNA-ENCODING A ERABUTOXIN-B FROM THE SEA-SNAKE LATICAUDA-SEMIFASCIATA Peer-reviewed

    K OBARA, N FUSE, T TSUCHIYA, Y NONOMURA, A MENEZ, T TAMIYA

    NUCLEIC ACIDS RESEARCH　17　(24)　10490-10490　1989/12

    DOI： 10.1093/nar/17.24.10490 　

    ISSN： 0305-1048

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Misc. 14

  1. 自然免疫の記憶における遺伝子発現制御

    布施直之

    生化学　96　277-280　2024/04

    DOI： 10.14952/SEIKAGAKU.2024.960277 　

  2. Re‐recognition of innate immune memory as an integrated multidimensional concept

    Chang Tang, Shoichiro Kurata, Naoyuki Fuse

    Microbiology and Immunology　67　(8)　355-364　2023/08

    Publisher: Wiley

    DOI： 10.1111/1348-0421.13083 　

    ISSN： 0385-5600 1348-0421

    eISSN： 1348-0421

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    Abstract In the past decade, the concept of immunological memory, which has long been considered a phenomenon observed in the adaptive immunity of vertebrates, has been extended to the innate immune system of various organisms. This de novo immunological memory is mainly called “innate immune memory”, “immune priming”, or “trained immunity” and has received increased attention because of its potential for clinical and agricultural applications. However, research on different species, especially invertebrates and vertebrates, has caused controversy regarding this concept. Here we discuss the current studies focusing on this immunological memory and summarize several mechanisms underlying it. We propose “innate immune memory” as a multidimensional concept as an integration between the seemingly different immunological phenomena.

  3. Regulation of gut starvation response through Drosophila NP3253 neurons International-journal

    NGUYEN Quang-Dat, 藤井希帆, 石橋謙太朗, 布施直之, 大坪和香子, 北澤春樹, 谷本拓, 倉田祥一朗

    日本分子生物学会年会プログラム・要旨集(Web)　46th　(2)　e70005　2023

    DOI： 10.1111/gtc.70005 　

    More details Close

    The "gut-brain axis," a bidirectional communication system between the gastrointestinal tract and the central nervous system, plays a crucial role in regulating complex physiological functions in response to nutrients, pathogens, and microbiota. However, the cellular and molecular mechanisms governing this regulation remain poorly understood. Using Drosophila melanogaster as a model organism, we previously identified NP3253 neurons, located in both the brain and gut, as key contributors to gut homeostasis during oral bacterial infection. Here, we found a novel role of NP3253 neurons in regulating starvation resistance. We observed that a subset of NP3253 neurons in the gut were activated during starvation. To investigate downstream effect, we conducted RNA-Seq analysis on the gut of adult flies with genetically silenced NP3253 neurons, comparing gene expression under starved and fed conditions. This analysis identified 26 genes differentially expressed in response to both starvation and NP3253 neuronal activity. Among these, CG12643, encoding an uncharacterized short peptide, was found to be essential for starvation resistance in the gut. Our findings demonstrate that NP3253 neurons modulate the gut gene expression in response to starvation, thereby supporting physiological adaptation to environmental stressors.

  4. Regulation of starvation response through neural control in Drosophila

    藤井希帆, NGUYEN Quang-Dat, 石橋謙太朗, 布施直之, 谷本拓, 北澤春樹, 大坪和香子, 倉田祥一朗

    日本分子生物学会年会プログラム・要旨集(Web)　46th　2023

  5. Genome research elucidating environmental adaptation: Dark-fly project as a case study Peer-reviewed

    Naoyuki Fuse

    CURRENT OPINION IN GENETICS & DEVELOPMENT　45　97-102　2017/08

    DOI： 10.1016/j.gde.2017.03.004 　

    ISSN： 0959-437X

    eISSN： 1879-0380

  6. Genome and traits of a Drosophila line evolved under a dark environment

    Naoyuki Fuse, Minako Izutsu, Yuzo Sugiyama, Osamu Nishimura, Kiyokazu Agata

    GENES & GENETIC SYSTEMS　87　(6)　382-382　2012/12

    ISSN： 1341-7568

    eISSN： 1880-5779

  7. 暗闇で長期間継代したショウジョウバエのゲノムと形質

    布施直之, 井筒弥那子, 杉山祐造, 西村理, 阿形清和

    日本遺伝学会大会プログラム・予稿集　84th　2012

  8. 暗闇で長期間継代したショウジョウバエのゲノムと形質

    布施直之, 前田真希, 辻本恵太, 井筒弥那子, 阿形清和

    日本分子生物学会年会プログラム・要旨集(Web)　35th　2012

  9. ショウジョウバエの暗闇環境への適応のメカニズム

    布施直之, 前田真希, 辻本恵太, 井筒弥那子, 杉山祐造, 西村理, 阿形清和

    生化学　2011

    ISSN： 0037-1017

  10. Adaptive behaviors of Drosophila in dark environment

    Keita Tsujimoto, Kohei Okamoto, Ryuichi Miyamoto, Maki Maeda, Kiyokazu Agata, Naoyuki Fuse

    NEUROSCIENCE RESEARCH　71　E343-E344　2011

    DOI： 10.1016/j.neures.2011.07.1507 　

    ISSN： 0168-0102

  11. ショウジョウバエの環境適応の分子メカニズム

    布施直之, 前田真希, 西村理, 杉山祐造, 辻本恵太, 井筒弥那子, 阿形清和

    生化学　2010

    ISSN： 0037-1017

  12. ショウジョウバエの暗所環境への適応進化

    布施直之, 岡本光平, 西村理, 前田真希, 宮本龍一, 杉山祐造, 山下真弘, 阿形清和

    日本分子生物学会年会講演要旨集　32nd　(Vol.1)　2009

  13. Cell size asymmetry and spindle orientation in asymmetric division of Drosophila nueroblasts

    F Matsuzaki, Y Izumi, N Fuse

    MOLECULAR BIOLOGY OF THE CELL　15　336A-336A　2004/11

    ISSN： 1059-1524

  14. PURIFICATION, CHARACTERIZATION AND SYNTHESIS OF NP-6, A NOVEL MEMBER OF RABBIT CORTICOSTATIC PEPTIDES

    N FUSE, Y HAYASHI, J FUKATA, T TOMINAGA, O EBISUI, Y SATOH, T ISOHARA, H IMURA

    PEPTIDE CHEMISTRY 1992　618-621　1993

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Research Projects 11

  1. 自然免疫の記憶におけるエピゲノム制御機構

    布施 直之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(C)

    Institution: 東北大学

    2023/04/01 - 2026/03/31

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    基本的な免疫機構である自然免疫には、長年、免疫記憶の仕組みが存在しないと考えられてきたが、近年、様々な生物で「自然免疫の記憶」が確認されている。しかし、そのメカニズムは未だ不明な点も多い。本研究は、ショウジョウバエを用いて、ゲノム、エピゲノム、トランスクリプトームを統合的に解析することで、「自然免疫の記憶」のメカニズムを明らかにすることを目的とした。 私達は、ショウジョウバエ(Drosophila melanogaster)を用いて免疫記憶を検出する実験系を構築した (Fuse et al., PLOS Genet, 2022)。ショウジョウバエにMicrococcus luteus（ルテウス菌）を感染させ訓練しておくと、その後、Staphylococcus aureus（黄色ブドウ球菌）を２次感染（本感染）させた後の生存率が有意に上昇することを見出した。すなわち、ルテウス菌は生ワクチンのように作用し、ショウジョウバエの感染抵抗性を増強していると考えられる。この実験系を用いて、私達はRNA-Seq解析を行い、免疫記憶における遺伝子発現制御を解析した。データベースの検索から、訓練によって本感染時の発現が上昇する遺伝子の発現制御にAda2bが関与する可能性が示唆された。Ada2bは、ヒストン修飾を制御するSAGA複合体の構成因子であることから、エピゲノム制御がショウジョウバエの免疫記憶に関与する可能性が示唆された。本研究では、Ada2bやSAGA複合体の役割を解析し、免疫記憶において免疫情報がどのようにエピゲノム情報に変換し、どのように遺伝子発現を制御するのか、明らかにする。

  2. Genome analysis for innate immune memory

    Fuse Naoyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2017/04/01 - 2020/03/31

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    Innate immunity is an evolutionarily conserved primitive defense system, and is currently realized to carry memory capacity of immune response as adaptive immunity does. However, its mechanism remains to be elusive. We study “innate immune memory” using fruit fly, Drosophila, that eliminates pathogens solely via innate immunity. Here, we found that comparing with naive flies, the flies trained to primary infection with some kinds of bacteria showed higher resistance against secondary infection with pathogenic bacteria. From RNA-Seq analysis, we identified 398 genes, whose expressions after secondary infection were up-regulated in training-dependent manners. These genes significantly enriched the immune genes regulated by Spt-Ada-Gcn5 acetyltransferase (SAGA), a histone modification complex. These results suggest that epigenetic reprogramming for gene expression might be involved in innate immune memory in insects as well as in mammals.

  3. Genome research elucidating environmental adaptation of Dark-fly

    Fuse Naoyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    2014/04/01 - 2017/03/31

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    Organisms are remarkably adapted to diverse environments, but molecular mechanism underlying environmental adaptation still remains elusive. To address this issue, we utilize a unique Drosophila line, "Dark-fly", which has been maintained for 62 years in a constant dark condition. We determined whole genome sequence of Dark-fly using next-generation sequencer and identified approximately 220,000 single nucleotide polymorphisms (SNPs) in the Dark-fly genome. To identify SNPs associated with dark-adaptation, we reared mixed populations of Dark-fly and the wild type fly in light and dark conditions. Our analyses of population genome detected environment-dependent selections of the Dark-fly genome. We consequently listed 84 candidate genes potentially involved in the adaptation of Dark-fly. We currently aim to clarify the roles of Dark-fly's SNPs in environmental adaptation using genome editing technology.

  4. 形態形成運動における三量体G蛋白質シグナルの調節機構

    布施 直之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 京都大学

    2008 - 2009

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    発生過程において、細胞は集団となってダイナミックに形を変え移動する。細胞運動の時空間制御に、三量体G蛋白質(G蛋白質)を介したシグナル伝達は重要な役割を果たしている。G蛋白質を介したシグナル伝逹はGPCRキナーゼ(GRK)などの多数の因子によって巧妙に調節されているが、シグナルの調節機構が形態形成運動にどのような役割をもつのか、わかっていない。本研究は、ショウジョウバエの原腸陥入をモデルに、形態形成におけるG蛋白質シグナルの調節機構の役割を明らかにすることを目的とする。私は、GRKの1つであるGprk2が原腸陥入に必須であることを見いだした。Gprk2の分子機能を解析することによって、形態形成におけるG蛋白質シグナルの調節機構を明らかにする。 Gprk2変異胚では、リガンドFogが制御するアピカル収縮の領域が広がっていた。FogとGprk2の2重変異がFog単独変異と同じ表現型を示すことから、Gprk2変異の表現型は異常なFogシグナルガ原因であることが示された。フランスのグループとの共同研究から、Fogのレセプターを同定し、Pogと名付けた。培養細胞を使った実験からGprk2はPogをリン酸化した。Gprk2のキナーゼ活性部位の1アミノ酸置換(K338R)は、Posをリン酸化する活性を失った。Gprk2変異胚における原腸陥入の異常は、野生型Gprk2によって救済されたが、(K338R)変異Gprk2によって救済されなかった。これらの結果は、Gprk2のキナーゼ活性が原腸陥入に必須であることを示すとともに、Gprk2によるPogのリン酸化がFogシグナルを調節し、細胞運動を時空間レベルで制御することが示唆された。今後、細胞運動におけるPogのリン酸化の影響を調べ、Gprk2の分子機能と役割の詳細を明らかにする。

  5. 形態形成運動を時空間レベルで制御する三量体Gタンパク質の活性化機構

    布施 直之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 国立遺伝学研究所

    2006 - 2007

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    発生過程において、細胞は集団となってダイナミックに形を変え移動する。このような形態形成運動では、個々の細胞の運動は時空間レベルで厳密に制御されなければならない。単独の細胞の運動において、三量体Gタンパク質(Gタンパク質)を介したシグナル伝達は重要な役割を果たしている。しかし、形態形成運動におけるGタンパク質の役割は不明な点が多い。また最近、Ric8やGRKなどのGタンパク質活性調節因子が多数同定されてきた。しかし、それらの因子によるGタンパク質の活性調節が形態形成運動にどのような役割をもつのか、わかっていない。本研究は、ショウジョウバエの原腸陥入をモデルに、形態形成運動におけるGタンパク質の役割と活性化機構を明らかにすることを目的とする。 G蛋白質シグナルの負の調節因子Gprk2の変異では、Gα12が制御する細胞運動が異常に広がるとともに、その細胞運動も途中で止まっていた。さらに、Gα12シグナルの出力であるミオシンの局在を解析するために、ミオシン軽鎖とGFPの融合タンパク質を発現し、ミオシンの局在変化をライブイメージングから定量化した。Gprk2変異では、ミオシンの局在変化がより早く起こるものの、その蓄積は低下した。これらの結果は、Gprk2がシグナルを抑制し細胞運動の領域を規定するとともに、シグナルの効率的な蓄積にも寄与し細胞運動を完了するために重要な役割を果たすことを示唆している。今後、キナーゼ活性をもつGprk2の基質を同定し、Gprk2の役割を明らかにする。

  6. Study on the asymmetric cell division of neural stem cells

    MATSUZAKI Fumio

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: RIKEN

    2002 - 2005

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    Drosophila neuroblasts provide an excellent platform to study asymmetric cell division and underlying cell polarity. Those cells undergo typical asymmetric divisions, during which cell-fate determinants localize to the basal cortex, mitotic spindles orient along the apical-basal axis, and unequal-sized daughter cells appear. In this study, we have carried out a large scale genetic screen to identify mutants defective in the neuroblasts asymmetric division. Among mutations that we identified in this study, mutations for new loci are classified as follows ; 1) Two mutations (4 alleles) disrupt cell size asymmetry between the daughters but not asymmetric localization of the determinants such as Miranda. 2) Three mutations (5 alleles) uncouple mitotic spindle orientation from the cell axis without affecting the cell polarity of neuroblasts. 3) One mutant is defective in correct orientation of the cell polarity relative to the underlying epithelia. 4) Two mutations cause an abnormal distribution of the cell fate determinants. The class 1 loci turned out to be genes encoding Gβ13F and Gyl subunits of heterotrimeric G proteins, respectively, which form a cortical complex, revealing that G protein signaling is involved in determining the ration in daughter cell size. We also revealed that the class 2 locus encodes the mushroom body defect (mud) gene, which had been identified from mutants defective in the adult brain organization. This finding provides a clue to elucidate a mechanism by which mitotic spindle orientation is coupled to cell polarity.

  7. Asymmetric cell division : mechanisms creating cell diversity from cell asymmetry

    MATSUZAKI Fumio, IZUMI Yasushi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (S)

    2001 - 2005

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    Drosophila neuroblasts undergo typical asymmetric divisions, during which cell-fate determinants localize to the basal cortex, mitotic spindles orient along the apical-basal axis, and unequal-sized daughter cells appear. We have carried out a large scale genetic screen to identify mutants defective in the neuroblasts asymmetric division. 1.Among several mutants showing novel phenotypes, two mutations disrupt cell size asymmetry between the daughters but not asymmetric localization of the determinants such as Miranda. These genes encode G□13F and G□1 subunits of heterotrimeric G proteins, respectively, which form a cortical complex. In the wild type neuroblasts, the basal spindle half is smaller than the apical one, forming the smaller basal daughter. In contrast, elimination of G□□ results in a large symmetric spindle in random orientations and causes division into nearly equal-sized cell, suggesting a critical role of G□□in asymmetric spindle organization in neuroblasts. 2.We also asked how spindle orientation is regulated by examining dividing epithelial cells and neuroblasts in those mutants ; it has been unclear because spindle orientation in neuroblasts is randomized by depleting any one of those components. It turned out that the spindle always points toward Pins location when it localizes asymmetrically, suggesting that Pines predominantly regulates spindle orientation. We are currently searching molecules acting with Pins to orient the mitotic spindle. By both genetic and biochemical screens, we identified Drosophila Mushroom body defect (Mud) as an essential factor in receptor-independent G protein signalling (Gαi and Pins) responsible for regulating spindle orientation in both cell types. Based on our study, we propose that Drosophila Mud, vertebrate NuMA and C.elegans Lin-5 play comparable roles in receptor-independent G-protein signalling and that these molecules, together with Pins GoLoco proteins and Gαi, constitute an essential part of a general mechanism regulating the mitotic spindle through interaction with astral microtubules.

  8. 神経幹細胞の非対称分裂に関与する遺伝子群の探索

    布施 直之

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 若手研究(B)

    2001 - 2002

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    ショウジョウバエの神経幹細胞は、非対称分裂を研究するよいモデルである。胚発生の時期に、神経幹細胞は表皮面に対して垂直方向に分裂し、大きさの異なる2つの娘細胞を生む。小さい娘細胞は神経前駆細胞の性質を獲得し、大きい娘細胞は元の幹細胞の性質を維持する。今までに、前駆細胞側への運命決定因子の分配などが明らかとなってきた。しかし、娘細胞の大きさの非対称性など、未解明の問題も多い。本研究は、大規模なスクリーニングから、神経幹細胞の非対称分裂に異常が起こる突然変異を同定し、非対称分裂のメカニズムを明らかにすることを目的とした。ethylmethane sulphonateを変異原として用いて、点突然変異を誘導し、劣性致死変異系統を作製した。運命決定因子のアダプター蛋白質Mirandaを指標にスクリーニングを行った。2100系統中6系統で、神経幹細胞の非対称分裂に異常が観察された。その内の1つは、既知のdiscs largeの変異系統であることがわかった。その他に、分裂軸が規定できない変異、Mirandaの局在と分裂軸が協調できない変異3系統、同じ大きさの娘細胞に等分裂する突然変異を同定した。この中から、同じ大きさの娘細胞に等分裂する突然変異に注目し、さらなる解析を行った。変異の神経幹細胞の分裂における微小管を観察したところ、本来起こる紡錘体の大きさの非対称性が失われ、両極とも安定した微小管を形成していた。ゲノムDNAの解析から、この突然変異の原因遺伝子は、三量体G蛋白質のβサブユニットをコードする、Gβ13F遺伝子であることがわかった。Gβ13Fの過剰発現は、分裂時の微小管の形成を阻害した。これらの結果から、極性をもった三量体G蛋白質のシグナルが微小管の形成に非対称性をつくり、非対称な紡錘体によって神経幹細胞が不等分裂していると考えられる。

  9. 細胞分裂に伴う転写因子の非対称分配の解析

    松崎 文雄, 布施 直之, 大城 朝一

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(A)

    Institution: 東北大学

    2000 - 2000

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    ショウジョウバエの神経幹細胞は、非対称に分裂する際、神経の運命決定因子である転写因子ProsperoやNotchシグナルの制御因子Numbを姉妹細胞に不等分配する。本研究では、そのメカニズムと背後にある細胞極性の分子実体を明らかにすることを目標とした。Prosperoのアダプター分子であるMirandaの細胞内局在をを指標として、神経幹細胞の非対称性を制御する因子を系統的に検索することを行った。その結果、がん抑制遺伝子giant larvae(lgl)及びdiscs large(dlg)の変異体で、Mirandaが神経幹細胞とその姉妹細胞に等しく分配されることが判明した。分子遺伝学的解析の結果次のことを我々は明らかにした。 1)この二つの遺伝子の変異体では、神経幹細胞の非対称分裂に際し、Mirandaはもとより、同様に不等分配されるNotchシグナルの抑制因子Numbも等分配されてしまう。従って、両者は、今まで知られている全ての神経運命決定因子の局在に必要とされる。 2)二つのがん抑制遺伝子は神経幹細胞の細胞表層に分布し、機能する。 3)両がん抑制因子の関係については、dlgがlglの局在に必要とされることから、dlgがlglの上位に位置すると考えられる。 4)lglの温度感受性変異株を用いた実験により、神経幹細胞の分裂期の開始後、まさに運命決定因子・アダプター分子複合体がbasal側に局在する過程にlglが機能する。 5)遺伝的な解析と薬理学的な方法から、lglは複数のmyosin分子種の活性を制御することにより、運命決定因子・アダプター分子複合体の細胞表層への局在に働くことが示唆された。

  10. 発生における非対称分裂の解析

    松崎 文雄, 布施 直之, 大城 朝一

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(A)

    Institution: 東北大学

    2000 - 2000

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    ショウジョウバエの神経幹細胞は、それ自身と姉妹細胞に非対称に分裂する際、神経の運命決定因子である転写因子ProsperoやNotchシグナルの制御因子Numbを姉妹細胞に不等分配する。これらの因子の不等分配は神経細胞の運命決定に必須なプロセスであり、本研究では、そのメカニズムと背後にある細胞極性の分子実体を明らかにすることを目標にしている。神経幹細胞の分裂に際して、アダプター分子であるMirandaがProsperoに直接結合し、その細胞内分布と不等分配を規定することを我々は明らかにしているが、そのMirandaの細胞内局在をを指標として、神経幹細胞の非対称性を制御する因子を系統的に検索することを行った。その結果、Mirandaが神経幹細胞とその姉妹細胞に等しく分配される突然変異をいくつか同定した。そのうち、ひとつについては、ショウジョウバエに脳腫瘍を引き起こすことが知られていたがん抑制遺伝子giant larvae(lgl)が原因遺伝子であることを突き止めた。さらに、他のがん抑制遺伝子を検索したところ、同じく脳腫瘍の原因遺伝子として知られるdiscs large(dlg)遺伝子の変異がlglと同一の表現型を示すことが判明した。両者は神経幹細胞の細胞表層に分布し、ProsperoとNumbの不等分配の両方に必要とされる。これらの事実から、これまでに知られている全ての神経運命決定因子を局在させる共通なプロセスが神経幹細胞には存在し、そこにdlg,lglが機能することが明らかにされた。遺伝的、および薬理学的な解析からは、lglが複数のmyosin分子種の活性を制御することにより、運命決定因子・アダプター分子複合体の細胞表層への局在に働くことが示唆される。この研究から、神経細胞の運命決定、分化因子の細胞内局在、がん抑制という従来関連が知られていなかった三つの現象に接点が見出された。

  11. Study of asymmetric division in development

    MATSUZAKI Fumio, FUSE Naoyuki, OHSHIRO Tomokazu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B).

    Institution: Tohoku University

    1999 - 2000

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    Asymmetric division is a basic mechanism for generating cellular diversity during development, and is often achieved by the asymmetric partition of cell fate determinants into one of two daughter cells. The Drosophila neural stem cells, neuroblasts, have been studied as a model system with which to investigate key aspects of this process, given that neural fate determinants such as Numb and Prospero are segregated into one of the two daughter cells generated by neuroblast division. Two important processes associated with the asymmetric division of neuroblasts are (1) the asymmetric localization of cell fate determinants, which is achieved by specific adapter proteins such as Miranda that themselves localize asymmetrically to the cortex, and (2) the orientation of the mitotic spindle and its coordination with the polarized localization of the determinants, which require the apical Baz-Insc-Pins complex. To understand the cell polarity underlying the asymmetric division of neuroblasts, we have screened for mutations that affect the localization of Miranda, and have revealed a previously unidentified mechanism responsible for the asymmetric localization of all known cell fate determinants during neuroblast division. This mechanism involves a cascade of two cortical tumor suppressor proteins, Lethal (2) giant larvae (Lgl) and Lethal (1) discs large (Dlg), and occurs upstream of the first and independently of the second of these two aspects of asymmetric division. Lgl and Dlg create intrinsic differences between sibling cells by mediating differential cortical protein targeting during mitosis, demonstrating for the first time a link between these tumor suppressor proteins and the asymmetric division of neural stem cells.

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