Details of the Researcher

PHOTO

Erina Kuranaga
Section
Graduate School of Life Sciences
Job title
Professor
Degree

  • 博士（医学）（大阪大学）

  • 修士（農学）（東京大学）

e-Rad No.
90376591

Research Areas 1

  • Life sciences / Molecular biology /

Papers 67

  1. Reduction of endocytosis and EGFR signaling is associated with the switch from isolated to clustered apoptosis during epithelial tissue remodeling in Drosophila

    Kevin Yuswan, Xiaofei Sun, Erina Kuranaga, Daiki Umetsu

    PLOS Biology　22　(10)　e3002823-e3002823　2024/10/14

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pbio.3002823 　

    eISSN： 1545-7885

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    Epithelial tissues undergo cell turnover both during development and for homeostatic maintenance. Removal of cells is coordinated with the increase in number of newly dividing cells to maintain barrier function of the tissue. In Drosophila metamorphosis, larval epidermal cells (LECs) are replaced by adult precursor cells called histoblasts. Removal of LECs must counterbalance the exponentially increasing adult histoblasts. Previous work showed that the LEC removal accelerates as endocytic activity decreases throughout all LECs. Here, we show that the acceleration is accompanied by a mode switching from isolated single-cell apoptosis to clustered ones induced by the endocytic activity reduction. We identify the epidermal growth factor receptor (EGFR) pathway via extracellular-signal regulated kinase (ERK) activity as the main components downstream of endocytic activity in LECs. The reduced ERK activity, caused by the decrease in endocytic activity, is responsible for the apoptotic mode switching. Initially, ERK is transiently activated in normal LECs surrounding a single apoptotic LEC in a ligand-dependent manner, preventing clustered cell death. Following the reduction of endocytic activity, LEC apoptosis events do not provoke these transient ERK up-regulations, resulting in the acceleration of the cell elimination rate by frequent clustered apoptosis. These findings contrasted with the common perspective that clustered apoptosis is disadvantageous. Instead, switching to clustered apoptosis is required to accommodate the growth of neighboring tissues.

  2. Calcium influx promotes PLEKHG4B localization to cell-cell junctions and regulates the integrity of junctional actin filaments. International-journal

    Komaki Ninomiya, Kai Ohta, Ukyo Kawasaki, Shuhei Chiba, Takanari Inoue, Erina Kuranaga, Kazumasa Ohashi, Kensaku Mizuno

    Molecular biology of the cell　mbcE23050154　2023/12/13

    DOI： 10.1091/mbc.E23-05-0154 　

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    PLEKHG4B is a Cdc42-targeting guanine-nucleotide exchange factor implicated in forming epithelial cell-cell junctions. Here we explored the mechanism regulating PLEKHG4B localization. PLEKHG4B localized to the basal membrane in normal Ca2+ medium but accumulated at cell-cell junctions upon ionomycin treatment. Ionomycin-induced junctional localization of PLEKHG4B was suppressed upon disrupting its annexin-A2 (ANXA2)-binding ability. Thus, Ca2+ influx and ANXA2 binding are crucial for PLEKHG4B localization to cell-cell junctions. Treatments with low Ca2+ or BAPTA-AM (an intracellular Ca2+ chelator) suppressed PLEKHG4B localization to the basal membrane. Mutations of the phosphoinositide-binding motif in the pleckstrin homology (PH) domain of PLEKHG4B or masking of membrane phosphatidylinositol-4,5-biphosphate [PI(4,5)P2] suppressed PLEKHG4B localization to the basal membrane, indicating that basal membrane localization of PLEKHG4B requires suitable intracellular Ca2+ levels and PI(4,5)P2 binding of the PH domain. Activation of mechanosensitive ion channels (MSCs) promoted PLEKHG4B localization to cell-cell junctions, and their inhibition suppressed it. Moreover, similar to the PLEKHG4B knockdown phenotypes, inhibition of MSCs or treatment with BAPTA-AM disturbed the integrity of actin filaments at cell-cell junctions. Taken together, our results suggest that Ca2+ influx plays crucial roles in PLEKHG4B localization to cell-cell junctions and the integrity of junctional actin organization, with MSCs contributing to this process. [Media: see text] [Media: see text].

  3. Drosophila innate immunity suppresses the survival of xenografted mammalian tumor cells

    Ayaka Aida, Kevin Yuswan, Yoichi Kawai, Keita Hasegawa, Yu-ichiro Nakajima, Erina Kuranaga

    Scientific Reports　13　(1)　2023/07/30

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-023-38489-9 　

    eISSN： 2045-2322

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    Abstract Patient-derived xenograft (PDX) is an emerging tool established in immunodeficient vertebrate models to assess individualized treatments for cancer patients. Current xenograft models are deficient in adaptive immune systems. However, the precise role of the innate immunity in the xenograft models is unknown. With conserved signaling pathways and established genetic tools, Drosophila has contributed to the understanding of the mechanism of tumor growth as well as tumor–host interactions for decades, making it a promising candidate model for studying whether or not the hosts’ innate immunity can accommodate transplanted human tumor cells. Here we show initial observations that assess the behavior and impact of several human tumor cell lines when transplanted into Drosophila. We found that some injected cell lines persisted for a longer duration and reduced hosts’ lifespan. In particular, the human lung cancer cell line A549 were observed adjacent to the fly host tissues. We examined two factors that affect the survivability of cancer cells: (1) the optimal temperature of each cell line and (2) the innate immunity of Drosophila hosts. Especially, transplanted human tumor cells survived longer in immunodeficient flies, suggesting that the host innate immune system impedes the growth of xenografted cells. Our attempts for xenografting fly models thus provide necessary steps to overcome for establishing PDX cancer models using invertebrates.

  4. Damage sensing mediated by serine proteases Hayan and Persephone for Toll pathway activation in apoptosis-deficient flies

    Shotaro Nakano, Soshiro Kashio, Kei Nishimura, Asuka Takeishi, Hina Kosakamoto, Fumiaki Obata, Erina Kuranaga, Takahiro Chihara, Yoshio Yamauchi, Toshiaki Isobe, Masayuki Miura

    PLOS Genetics　19　(6)　e1010761-e1010761　2023/06/15

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pgen.1010761 　

    eISSN： 1553-7404

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    The mechanisms by which the innate immune system senses damage have been extensively explored in multicellular organisms. In Drosophila, various types of tissue damage, including epidermal injury, tumor formation, cell competition, and apoptosis deficiency, induce sterile activation of the Toll pathway, a process that requires the use of extracellular serine protease (SP) cascades. Upon infection, the SP Spätzle (Spz)-processing enzyme (SPE) cleaves and activates the Toll ligand Spz downstream of two paralogous SPs, Hayan and Persephone (Psh). However, upon tissue damage, it is not fully understood which SPs establish Spz activation cascades nor what damage-associated molecules can activate SPs. In this study, using newly generated uncleavable spz mutant flies, we revealed that Spz cleavage is required for the sterile activation of the Toll pathway, which is induced by apoptosis-deficient damage of wing epidermal cells in adult Drosophila. Proteomic analysis of hemolymph, followed by experiments with Drosophila Schneider 2 (S2) cells, revealed that among hemolymph SPs, both SPE and Melanization Protease 1 (MP1) have high capacities to cleave Spz. Additionally, in S2 cells, MP1 acts downstream of Hayan and Psh in a similar manner to SPE. Using genetic analysis, we found that the upstream SPs Hayan and Psh contributes to the sterile activation of the Toll pathway. While SPE/MP1 double mutants show more impairment of Toll activation upon infection than SPE single mutants, Toll activation is not eliminated in these apoptosis-deficient flies. This suggests that Hayan and Psh sense necrotic damage, inducing Spz cleavage by SPs other than SPE and MP1. Furthermore, hydrogen peroxide, a representative damage-associated molecule, activates the Psh-Spz cascade in S2 cells overexpressing Psh. Considering that reactive oxygen species (ROS) were detected in apoptosis-deficient wings, our findings highlight the importance of ROS as signaling molecules that induce the activation of SPs such as Psh in response to damage.

  5. Nutrient-driven dedifferentiation of enteroendocrine cells promotes adaptive intestinal growth

    Hiroki Nagai, Luis Augusto Eijy Nagai, Sohei Tasaki, Ryuichiro Nakato, Daiki Umetsu, Erina Kuranaga, Masayuki Miura, Yu-ichiro Nakajima

    2023/05/08

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2023.05.08.539820 　

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    SUMMARY Post-developmental organ resizing improves organismal fitness under constantly changing nutrient environments. Although stem cell abundance is a fundamental determinant of adaptive resizing, our understanding of its underlying mechanisms remains primarily limited to the regulation of stem cell division. Here we demonstrate that nutrient fluctuation induces dedifferentiation in theDrosophilaadult midgut to drive adaptive intestinal growth. From lineage tracing and single-cell RNA-sequencing, we identify a subpopulation of enteroendocrine cells (EEs) that convert into functional intestinal stem cells (ISCs) in response to dietary glucose and amino acids by activating the JAK-STAT pathway. Genetic ablation of EE-derived ISCs severely impairs ISC expansion and midgut growth despite the retention of resident ISCs, andin silicomodeling further indicates that EE dedifferentiation enables efficient increase in the midgut cell number while maintaining epithelial cell composition. Our findings uncover a physiologically-induced dedifferentiation that ensures ISC expansion during adaptive organ growth in concert with nutrient conditions.

  6. Underlying mechanisms that ensure actomyosin‐mediated directional remodeling of cell–cell contacts for multicellular movement

    Hiroyuki Uechi, Erina Kuranaga

    BioEssays　2200211-2200211　2023/03/17

    Publisher: Wiley

    DOI： 10.1002/bies.202200211 　

    ISSN： 0265-9247

    eISSN： 1521-1878

  7. Distinct stem-like cell populations facilitate functional regeneration of theCladonemamedusa tentacle

    Sosuke Fujita, Erina Kuranaga, Masayuki Miura, Yu-ichiro Nakajima

    2022/12/11

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2022.12.11.519944 　

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    Abstract Blastema formation is a crucial process that provides a cellular source for regenerating tissues and organs. While bilaterians have diversified blastema formation methods, its mechanisms in non-bilaterians remain poorly understood. Cnidarian jellyfish, or medusae, represent early-branching metazoans that exhibit complex morphology and possess defined appendage structures highlighted by tentacles with stinging cells (nematocytes). Here we investigate the mechanisms of tentacle regeneration, using the hydrozoan jellyfishCladonema pacificum. We show that proliferative cells accumulate at the tentacle amputation site and form a blastema composed of cells with stem-like cell morphology. Lineage tracing experiments indicate that repair-specific proliferative cells in the blastema are distinct from resident stem-like cells. We further demonstrate that resident stem-like cells control nematogenesis and tentacle elongation during both homeostasis and regeneration, while repair-specific proliferative cells preferentially differentiate into epithelial cells in the newly formed tentacle, analogous to lineage-restricted stem/progenitor cells observed in salamander limbs. Taken together, our findings reveal a regeneration mechanism that utilizes both resident stem-like cells and repair-specific proliferative cells, which in conjunction efficiently enable functional appendage regeneration, and provide novel insight into the diversification of blastema formation across animal evolution.

  8. Fluorescent <em>In Situ</em> Hybridization and 5-Ethynyl-2'-Deoxyuridine Labeling for Stem-like Cells in the Hydrozoan Jellyfish <em>Cladonema pacificum</em>

    Sosuke Fujita, Erina Kuranaga, Masayuki Miura, Yu-ichiro Nakajima

    Journal of Visualized Experiments　(186)　2022/08/03

    Publisher: MyJove Corporation

    DOI： 10.3791/64285 　

    eISSN： 1940-087X

  9. Inhibition of negative feedback for persistent epithelial cell-cell junction contraction by p21-activated kinase 3. International-journal

    Hiroyuki Uechi, Kazuki Fukushima, Ryota Shirasawa, Sayaka Sekine, Erina Kuranaga

    Nature communications　13　(1)　3520-3520　2022/06/20

    DOI： 10.1038/s41467-022-31252-0 　

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    Actin-mediated mechanical forces are central drivers of cellular dynamics. They generate protrusive and contractile dynamics, the latter of which are induced in concert with myosin II bundled at the site of contraction. These dynamics emerge concomitantly in tissues and even each cell; thus, the tight regulation of such bidirectional forces is important for proper cellular deformation. Here, we show that contractile dynamics can eventually disturb cell-cell junction contraction in the absence of p21-activated kinase 3 (Pak3). Upon Pak3 depletion, contractility induces the formation of abnormal actin protrusions at the shortening junctions, which causes decrease in E-cadherin levels at the adherens junctions and mislocalization of myosin II at the junctions before they enough shorten, compromising completion of junction shortening. Overexpressing E-cadherin restores myosin II distribution closely placed at the junctions and junction contraction. Our results suggest that contractility both induces and perturbs junction contraction and that the attenuation of such perturbations by Pak3 facilitates persistent junction shortening.

  10. siRNA-mediated gene knockdown via electroporation in hydrozoan jellyfish embryos

    Tokiha Masuda-Ozawa, Sosuke Fujita, Ryotaro Nakamura, Hiroshi Watanabe, Erina Kuranaga, Yu-ichiro Nakajima

    2022/03/27

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2022.03.24.485716 　

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    Abstract As the sister group to bilaterians, cnidarians stand in a unique phylogenetic position that provides insight into evolutionary aspects of animal development, physiology, and behavior. While cnidarians are classified into two types, sessile polyps and free-swimming medusae, most studies at the cellular and molecular levels have been conducted on representative polyp-type cnidarians and have focused on establishing techniques of genetic manipulation. Recently, gene knockdown by delivery of short hairpin RNAs into eggs via electroporation has been introduced in two polyp-type cnidarians, Nematostella vectensis and Hydractinia symbiolongicarpus, enabling systematic loss-of-function experiments. By contrast, current methods of genetic manipulation for most medusa-type cnidarians, or jellyfish, are quite limited, except for Clytia hemisphaerica, and reliable techniques are required to interrogate function of specific genes in different jellyfish species. Here, we present a method to knock down target genes by delivering small interfering RNA (siRNA) into fertilized eggs via electroporation, using the hydrozoan jellyfish, Clytia hemisphaerica and Cladonema paciificum. We show that siRNAs targeting endogenous GFP1 and Wnt3 in Clytia efficiently knock down gene expression and result in known planula phenotypes: loss of green fluorescence and defects in axial patterning, respectively. We also successfully knock down endogenous Wnt3 in Cladonema by siRNA electroporation, which circumvents the technical difficulty of microinjecting small eggs. Wnt3 knockdown in Cladonema causes gene expression changes in axial markers, suggesting a conserved Wnt/β-catenin-mediated pathway that controls axial polarity during embryogenesis. Our gene-targeting siRNA electroporation method is applicable to other animals, including and beyond jellyfish species, and will facilitate the investigation and understanding of myriad aspects of animal development.

  11. Regeneration Potential of Jellyfish: Cellular Mechanisms and Molecular Insights

    Sosuke Fujita, Erina Kuranaga, Yu-ichiro Nakajima

    Genes　12　(5)　758-758　2021/05/17

    Publisher: MDPI AG

    DOI： 10.3390/genes12050758 　

    eISSN： 2073-4425

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    Medusozoans, the Cnidarian subphylum, have multiple life stages including sessile polyps and free-swimming medusae or jellyfish, which are typically bell-shaped gelatinous zooplanktons that exhibit diverse morphologies. Despite having a relatively complex body structure with well-developed muscles and nervous systems, the adult medusa stage maintains a high regenerative ability that enables organ regeneration as well as whole body reconstitution from the part of the body. This remarkable regeneration potential of jellyfish has long been acknowledged in different species; however, recent studies have begun dissecting the exact processes underpinning regeneration events. In this article, we introduce the current understanding of regeneration mechanisms in medusae, particularly focusing on cellular behaviors during regeneration such as wound healing, blastema formation by stem/progenitor cells or cell fate plasticity, and the organism-level patterning that restores radial symmetry. We also discuss putative molecular mechanisms involved in regeneration processes and introduce a variety of novel model jellyfish species in the effort to understand common principles and diverse mechanisms underlying the regeneration of complex organs and the entire body.

  12. Pins Suppresses Abnormal Cell Fate Reprogramming During Wing Regeneration in <i>Drosophila</i>

    Fumiya Ishihara, Erina Kuranaga, Yuichiro Nakajima

    SSRN Electronic Journal　2021

    Publisher: Elsevier BV

    DOI： 10.2139/ssrn.3924628 　

    eISSN： 1556-5068

  13. Differential cell adhesion implemented by Drosophila Toll corrects local distortions of the anterior-posterior compartment boundary. International-journal Peer-reviewed

    Norihiro Iijima, Katsuhiko Sato, Erina Kuranaga, Daiki Umetsu

    Nature communications　11　(1)　6320-6320　2020/12/10

    DOI： 10.1038/s41467-020-20118-y 　

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    Maintaining lineage restriction boundaries in proliferating tissues is vital to animal development. A long-standing thermodynamics theory, the differential adhesion hypothesis, attributes cell sorting phenomena to differentially expressed adhesion molecules. However, the contribution of the differential adhesion system during tissue morphogenesis has been unsubstantiated despite substantial theoretical support. Here, we report that Toll-1, a transmembrane receptor protein, acts as a differentially expressed adhesion molecule that straightens the fluctuating anteroposterior compartment boundary in the abdominal epidermal epithelium of the Drosophila pupa. Toll-1 is expressed across the entire posterior compartment under the control of the selector gene engrailed and displays a sharp expression boundary that coincides with the compartment boundary. Toll-1 corrects local distortions of the boundary in the absence of cable-like Myosin II enrichment along the boundary. The reinforced adhesion of homotypic cell contacts, together with pulsed cell contraction, achieves a biased vertex sliding action by resisting the separation of homotypic cell contacts in boundary cells. This work reveals a self-organizing system that integrates a differential adhesion system with pulsed contraction of cells to maintain lineage restriction boundaries.

  14. Reduction of endocytic activity accelerates cell elimination during tissue remodeling of the Drosophila epidermal epithelium. International-journal Peer-reviewed

    Shinichiro Hoshika, Xiaofei Sun, Erina Kuranaga, Daiki Umetsu

    Development (Cambridge, England)　147　(7)　2020/04/14

    DOI： 10.1242/dev.179648 　

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    Epithelial tissues undergo cell turnover both during development and for homeostatic maintenance. Cells that are no longer needed are quickly removed without compromising the barrier function of the tissue. During metamorphosis, insects undergo developmentally programmed tissue remodeling. However, the mechanisms that regulate this rapid tissue remodeling are not precisely understood. Here, we show that the temporal dynamics of endocytosis modulate physiological cell properties to prime larval epidermal cells for cell elimination. Endocytic activity gradually reduces as tissue remodeling progresses. This reduced endocytic activity accelerates cell elimination through the regulation of Myosin II subcellular reorganization, junctional E-cadherin levels, and caspase activation. Whereas the increased Myosin II dynamics accelerates cell elimination, E-cadherin plays a protective role against cell elimination. Reduced E-cadherin is involved in the amplification of caspase activation by forming a positive-feedback loop with caspase. These findings reveal the role of endocytosis in preventing cell elimination and in the cell-property switching initiated by the temporal dynamics of endocytic activity to achieve rapid cell elimination during tissue remodeling.

  15. The Tricellular Junction Protein Sidekick Regulates Vertex Dynamics to Promote Bicellular Junction Extension. International-journal Peer-reviewed

    Hiroyuki Uechi, Erina Kuranaga

    Developmental cell　50　(3)　327-338　2019/08/05

    DOI： 10.1016/j.devcel.2019.06.017 　

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    Remodeling of cell-cell junctions drives cell intercalation that causes tissue movement during morphogenesis through the shortening and growth of bicellular junctions. The growth of new junctions is essential for continuing and then completing cellular dynamics and tissue shape sculpting; however, the mechanism underlying junction growth remains obscure. We investigated Drosophila genitalia rotation where continuous cell intercalation occurs to show that myosin II accumulating at the vertices of a new junction is required for the junction growth. This myosin II accumulation requires the adhesive transmembrane protein Sidekick (Sdk), which localizes to the adherens junctions (AJs) of tricellular contacts (tAJs). Sdk also localizes to and blocks the accumulation of E-Cadherin at newly formed growing junctions, which maintains the growth rate. We propose that Sdk facilitates tAJ movement by mediating myosin II-driven contraction and altering the adhesive properties at the tAJs, leading to cell-cell junction extension during persistent junction remodeling.

  16. Apical Junctional Fluctuations Lead to Cell Flow while Maintaining Epithelial Integrity. International-journal Peer-reviewed

    Satoru Okuda, Erina Kuranaga, Katsuhiko Sato

    Biophysical journal　116　(6)　1159-1170　2019/03/19

    DOI： 10.1016/j.bpj.2019.01.039 　

    ISSN： 0006-3495

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    Epithelial sheet integrity is robustly maintained during morphogenesis, which is essential to shape organs and embryos. While maintaining the planar monolayer in three-dimensional space, cells dynamically flow via rearranging their connections between each other. However, little is known about how cells maintain the plane sheet integrity in three-dimensional space and provide cell flow in the in-plane sheet. In this study, using a three-dimensional vertex model, we demonstrate that apical junctional fluctuations allow stable cell rearrangements while ensuring monolayer integrity. In addition to the fluctuations, direction-dependent contraction on the apical cell boundaries, which corresponds to forces from adherens junctions, induces cell flow in a definite direction. We compared the kinematic behaviors of this apical-force-driven cell flow with those of typical cell flow that is driven by forces generated on basal regions and revealed the characteristic differences between them. These differences can be used to distinguish the mechanism of epithelial cell flow observed in experiments, i.e., whether it is apical- or basal-force-driven. Our numerical simulations suggest that cells actively generate fluctuations and use them to regulate both epithelial integrity and plasticity during morphogenesis.

  17. Cell proliferation controls body size growth, tentacle morphogenesis, and regeneration in hydrozoan jellyfish Cladonema pacificum. International-journal Peer-reviewed

    Sosuke Fujita, Erina Kuranaga, Yu-Ichiro Nakajima

    PeerJ　7　e7579　2019

    DOI： 10.7717/peerj.7579 　

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    Jellyfish have existed on the earth for around 600 million years and have evolved in response to environmental changes. Hydrozoan jellyfish, members of phylum Cnidaria, exist in multiple life stages, including planula larvae, vegetatively-propagating polyps, and sexually-reproducing medusae. Although free-swimming medusae display complex morphology and exhibit increase in body size and regenerative ability, their underlying cellular mechanisms are poorly understood. Here, we investigate the roles of cell proliferation in body-size growth, appendage morphogenesis, and regeneration using Cladonema pacificum as a hydrozoan jellyfish model. By examining the distribution of S phase cells and mitotic cells, we revealed spatially distinct proliferating cell populations in medusae, uniform cell proliferation in the umbrella, and clustered cell proliferation in tentacles. Blocking cell proliferation by hydroxyurea caused inhibition of body size growth and defects in tentacle branching, nematocyte differentiation, and regeneration. Local cell proliferation in tentacle bulbs is observed in medusae of two other hydrozoan species, Cytaeis uchidae and Rathkea octopunctata, indicating that it may be a conserved feature among hydrozoan jellyfish. Altogether, our results suggest that hydrozoan medusae possess actively proliferating cells and provide experimental evidence regarding the role of cell proliferation in body-size control, tentacle morphogenesis, and regeneration.

  18. Mathematical Modeling of Tissue Folding and Asymmetric Tissue Flow during Epithelial Morphogenesis. Invited Peer-reviewed

    Tetsuya Hiraiwa, Fu-Lai Wen, Tatsuo Shibata, Erina Kuranaga

    Symmetry　11　(1)　113-113　2019

    DOI： 10.3390/sym11010113 　

  19. Mechanisms of unusual collective cell movement lacking a free front edge in Drosophila. International-journal Peer-reviewed

    Hiroyuki Uechi, Erina Kuranaga

    Current opinion in genetics & development　51　46-51　2018/08

    DOI： 10.1016/j.gde.2018.06.012 　

    ISSN： 0959-437X

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    The shape and structure of tissues are generated by the dynamic behavior of various cell collectives during morphogenesis. These behaviors include collective cell movement, in which cells move coordinately in a given direction while maintaining cell-cell attachments throughout the collective. For a cell collective to acquire mobility, the cell collective generates forces, and the cells in the front sense extrinsic cues to decide the direction of the movement. However, some collectives that fill a confined space move even though they lack such front cells. These dynamic cell behaviors have been studied in detail in egg chamber rotation and male genitalia rotation in Drosophila; however, similar phenomena are found in mammals. Here we review how the movements of such front-edgeless cell collectives are generated.

  20. Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology. International-journal Peer-reviewed

    Alice Tsuboi, Shizue Ohsawa, Daiki Umetsu, Yukari Sando, Erina Kuranaga, Tatsushi Igaki, Koichi Fujimoto

    Current biology : CB　28　(13)　2115-2128　2018/07/09

    DOI： 10.1016/j.cub.2018.05.029 　

    ISSN： 0960-9822

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    During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation.

  21. Ubiquitin-Binding Protein CG5445 Suppresses Aggregation and Cytotoxicity of Amyotrophic Lateral Sclerosis-Linked TDP-43 in Drosophila. International-journal Peer-reviewed

    Hiroyuki Uechi, Erina Kuranaga, Tomohiro Iriki, Kohei Takano, Shoshiro Hirayama, Masayuki Miura, Jun Hamazaki, Shigeo Murata

    Molecular and cellular biology　38　(3)　2018/02/01

    Publisher: American Society for Microbiology

    DOI： 10.1128/MCB.00195-17 　

    ISSN： 1098-5549 0270-7306

  22. Mechanisms of collective cell movement lacking a leading or free front edge in vivo. International-journal Peer-reviewed

    Hiroyuki Uechi, Erina Kuranaga

    Cellular and molecular life sciences : CMLS　74　(15)　2709-2722　2017/08

    DOI： 10.1007/s00018-017-2489-x 　

    ISSN： 1420-682X

    eISSN： 1420-9071

  23. Planar polarized contractile actomyosin networks in dynamic tissue morphogenesis. International-journal Peer-reviewed

    Daiki Umetsu, Erina Kuranaga

    Current opinion in genetics & development　45　90-96　2017/08

    DOI： 10.1016/j.gde.2017.03.012 　

    ISSN： 0959-437X

    eISSN： 1879-0380

  24. Caspase-dependent non-apoptotic processes in development. International-journal Peer-reviewed

    Yu-Ichiro Nakajima, Erina Kuranaga

    Cell death and differentiation　24　(8)　1422-1430　2017/08

    DOI： 10.1038/cdd.2017.36 　

    ISSN： 1350-9047

    eISSN： 1476-5403

  25. Wave Propagation of Junctional Remodeling in Collective Cell Movement of Epithelial Tissue: Numerical Simulation Study. International-journal Peer-reviewed

    Tetsuya Hiraiwa, Erina Kuranaga, Tatsuo Shibata

    Frontiers in cell and developmental biology　5　66-66　2017

    Publisher: Frontiers Media S.A.

    DOI： 10.3389/fcell.2017.00066 　

    ISSN： 2296-634X

  26. Inference of Cell Mechanics in Heterogeneous Epithelial Tissue Based on Multivariate Clone Shape Quantification. International-journal Peer-reviewed

    Alice Tsuboi, Daiki Umetsu, Erina Kuranaga, Koichi Fujimoto

    Frontiers in cell and developmental biology　5　68-68　2017

    Publisher: Frontiers Media S.A.

    DOI： 10.3389/fcell.2017.00068 　

    ISSN： 2296-634X

  27. Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors. International-journal Peer-reviewed

    Yuhei Kawamoto, Yu-Ichiro Nakajima, Erina Kuranaga

    International journal of molecular sciences　17　(12)　2016/12/20

    DOI： 10.3390/ijms17122144 　

    ISSN： 1422-0067

  28. Left-right asymmetric cell intercalation drives directional collective cell movement in epithelial morphogenesis. International-journal Peer-reviewed

    Katsuhiko Sato, Tetsuya Hiraiwa, Emi Maekawa, Ayako Isomura, Tatsuo Shibata, Erina Kuranaga

    Nature communications　6　10074-10074　2015/12/10

    DOI： 10.1038/ncomms10074 　

    ISSN： 2041-1723

  29. Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. International-journal Peer-reviewed

    Ting Liu, Yoshifumi Yamaguchi, Yoshitaka Shirasaki, Koichi Shikada, Mai Yamagishi, Katsuaki Hoshino, Tsuneyasu Kaisho, Kiwamu Takemoto, Toshihiko Suzuki, Erina Kuranaga, Osamu Ohara, Masayuki Miura

    Cell reports　8　(4)　974-82　2014/08/21

    DOI： 10.1016/j.celrep.2014.07.012 　

    ISSN： 2211-1247

  30. Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis. International-journal Peer-reviewed

    Fumiaki Obata, Erina Kuranaga, Katsura Tomioka, Ming Ming, Asuka Takeishi, Chun-Hong Chen, Tomoyoshi Soga, Masayuki Miura

    Cell reports　7　(3)　821-33　2014/05/08

    DOI： 10.1016/j.celrep.2014.03.046 　

    ISSN： 2211-1247

  31. Persephone/Spätzle pathogen sensors mediate the activation of Toll receptor signaling in response to endogenous danger signals in apoptosis-deficient Drosophila. International-journal Peer-reviewed

    Ming Ming, Fumiaki Obata, Erina Kuranaga, Masayuki Miura

    The Journal of biological chemistry　289　(11)　7558-68　2014/03/14

    DOI： 10.1074/jbc.M113.543884 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  32. In vivo monitoring of caspase activation using a fluorescence resonance energy transfer-based fluorescent probe. International-journal Peer-reviewed

    Yoshifumi Yamaguchi, Erina Kuranaga, Yu-Ichiro Nakajima, Akiko Koto, Kiwamu Takemoto, Masayuki Miura

    Methods in enzymology　544　299-325　2014

    DOI： 10.1016/B978-0-12-417158-9.00012-1 　

    ISSN： 0076-6879

  33. RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy. International-journal Peer-reviewed

    Ryoko Ihara, Koji Matsukawa, Yusei Nagata, Hayato Kunugi, Shoji Tsuji, Takahiro Chihara, Erina Kuranaga, Masayuki Miura, Tomoko Wakabayashi, Tadafumi Hashimoto, Takeshi Iwatsubo

    Human molecular genetics　22　(22)　4474-84　2013/11/15

    DOI： 10.1093/hmg/ddt296 　

    ISSN： 0964-6906

    More details Close

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities in RNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy.

  34. Homeostatic Epithelial Renewal in the Gut Is Required for Dampening a Fatal Systemic Wound Response in Drosophila Peer-reviewed

    Asuka Takeishi, Erina Kuranaga, Ayako Tonoki, Kazuyo Misaki, Shigenobu Yonemura, Hirotaka Kanuka, Masayuki Miura

    CELL REPORTS　3　(3)　919-930　2013/03

    DOI： 10.1016/j.celrep.2013.02.022 　

    ISSN： 2211-1247

  35. The Kelch Repeat Protein KLHDC10 Regulates Oxidative Stress-Induced ASK1 Activation by Suppressing PP5 Peer-reviewed

    Yusuke Sekine, Ryo Hatanaka, Takeshi Watanabe, Naoki Sono, Shun-ichiro Iemura, Tohru Natsume, Erina Kuranaga, Masayuki Miura, Kohsuke Takeda, Hidenori Ichijo

    MOLECULAR CELL　48　(5)　692-704　2012/12

    DOI： 10.1016/j.molcel.2012.09.018 　

    ISSN： 1097-2765

    eISSN： 1097-4164

  36. Beyond apoptosis: caspase regulatory mechanisms and functions in vivo Peer-reviewed

    Erina Kuranaga

    GENES TO CELLS　17　(2)　83-97　2012/02

    DOI： 10.1111/j.1365-2443.2011.01579.x 　

    ISSN： 1356-9597

  37. p38 MAPKs regulate the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors Peer-reviewed

    Yusuke Sekine, Shuichi Takagahara, Ryo Hatanaka, Takeshi Watanabe, Haruka Oguchi, Takuya Noguchi, Isao Naguro, Kazuto Kobayashi, Makoto Tsunoda, Takashi Funatsu, Hiroshi Nomura, Takeshi Toyoda, Norio Matsuki, Erina Kuranaga, Masayuki Miura, Kohsuke Takeda, Hidenori Ichijo

    JOURNAL OF CELL SCIENCE　124　(17)　3006-3016　2011/09

    DOI： 10.1242/jcs.085902 　

    ISSN： 0021-9533

    eISSN： 1477-9137

  38. beta-Galactosidase Fluorescence Probe with Improved Cellular Accumulation Based on a Spirocyclized Rhodol Scaffold Peer-reviewed

    Mako Kamiya, Daisuke Asanuma, Erina Kuranaga, Asuka Takeishi, Masayo Sakabe, Masayuki Miura, Tetsuo Nagano, Yasuteru Urano

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY　133　(33)　12960-12963　2011/08

    DOI： 10.1021/ja204781t 　

    ISSN： 0002-7863

  39. Nonautonomous Apoptosis Is Triggered by Local Cell Cycle Progression during Epithelial Replacement in Drosophila Peer-reviewed

    Yu-ichiro Nakajima, Erina Kuranaga, Kaoru Sugimura, Atsushi Miyawaki, Masayuki Miura

    MOLECULAR AND CELLULAR BIOLOGY　31　(12)　2499-2512　2011/06

    DOI： 10.1128/MCB.01046-10 　

    ISSN： 0270-7306

  40. Aging causes distinct characteristics of polyglutamine amyloids in vivo Peer-reviewed

    Ayako Tonoki, Erina Kuranaga, Natsuki Ito, Yoko Nekooki-Machida, Motomasa Tanaka, Masayuki Miura

    GENES TO CELLS　16　(5)　557-564　2011/05

    DOI： 10.1111/j.1365-2443.2011.01505.x 　

    ISSN： 1356-9597

  41. Apoptosis controls the speed of looping morphogenesis in Drosophila male terminalia. International-journal Peer-reviewed

    Erina Kuranaga, Takayuki Matsunuma, Hirotaka Kanuka, Kiwamu Takemoto, Akiko Koto, Ken-ichi Kimura, Masayuki Miura

    Development (Cambridge, England)　138　(8)　1493-9　2011/04

    DOI： 10.1242/dev.058958 　

    ISSN： 0950-1991

    More details Close

    In metazoan development, the precise mechanisms that regulate the completion of morphogenesis according to a developmental timetable remain elusive. The Drosophila male terminalia is an asymmetric looping organ; the internal genitalia (spermiduct) loops dextrally around the hindgut. Mutants for apoptotic signaling have an orientation defect of their male terminalia, indicating that apoptosis contributes to the looping morphogenesis. However, the physiological roles of apoptosis in the looping morphogenesis of male terminalia have been unclear. Here, we show the role of apoptosis in the organogenesis of male terminalia using time-lapse imaging. In normal flies, genitalia rotation accelerated as development proceeded, and completed a full 360° rotation. This acceleration was impaired when the activity of caspases or JNK or PVF/PVR signaling was reduced. Acceleration was induced by two distinct subcompartments of the A8 segment that formed a ring shape and surrounded the male genitalia: the inner ring rotated with the genitalia and the outer ring rotated later, functioning as a 'moving walkway' to accelerate the inner ring rotation. A quantitative analysis combining the use of a FRET-based indicator for caspase activation with single-cell tracking showed that the timing and degree of apoptosis correlated with the movement of the outer ring, and upregulation of the apoptotic signal increased the speed of genital rotation. Therefore, apoptosis coordinates the outer ring movement that drives the acceleration of genitalia rotation, thereby enabling the complete morphogenesis of male genitalia within a limited developmental time frame.

  42. Apoptosis Ensures Spacing Pattern Formation of Drosophila Sensory Organs Peer-reviewed

    Akiko Koto, Erina Kuranaga, Masayuki Miura

    CURRENT BIOLOGY　21　(4)　278-287　2011/02

    DOI： 10.1016/j.cub.2011.01.015 　

    ISSN： 0960-9822

  43. Caspase signaling in animal development Peer-reviewed

    Erina Kuranaga

    DEVELOPMENT GROWTH & DIFFERENTIATION　53　(2)　137-148　2011/02

    DOI： 10.1111/j.1440-169X.2010.01237.x 　

    ISSN： 0012-1592

  44. 2SC-04 Imaging analysis of cellular dynamics for organogenesis(2SC Whole body imaging,The 49th Annual Meeting of the Biophysical Society of Japan)

    Kuranaga Erina

    Seibutsu Butsuri　51　S16　2011

    Publisher: The Biophysical Society of Japan General Incorporated Association

    DOI： 10.2142/biophys.51.S16_2 　

  45. [Genetic approach for understanding of the late-onset mechanisms of polyglutamine disease]. Peer-reviewed

    Erina Kuranaga, Ayako Tonoki, Masayuki Miura

    Rinsho shinkeigaku = Clinical neurology　49　(11)　910-2　2009/11

    Publisher: 11

    DOI： 10.5692/clinicalneurol.49.910 　

    ISSN： 0009-918X

    More details Close

    The intracellular accumulation of unfolded or misfolded proteins is believed to contribute to aging and age-related neurodegenerative diseases. However, the links between age-dependent proteotoxicity and cellular protein degradation systems remain poorly understood. Here, we show that 26S proteasome activity and abundance attenuate with age, which is associated with the impaired assembly of the 26S proteasome with the 19S regulatory particle (RP) and the 20S proteasome. In a genetic gain-of-function screen using Drosophila, we characterized Rpn11, which encodes a subunit of the 19S RP, as a suppressor of expanded polyglutamine-induced progressive neurodegeneration. Rpn11 overexpression suppressed the age-related reduction of the 26S proteasome activity, resulting in the extension of flies' life spans with suppression of the age-dependent accumulation of ubiquitinated proteins. On the other hand, the loss of function of Rpn11 caused an early onset of reduced 26S proteasome activity and a premature age-dependent accumulation of ubiquitinated proteins. It also caused a shorter life span and an enhanced neurodegenerative phenotype. Our results suggest that maintaining the 26S proteasome with age could extend the life span and suppress the age-related progression of polyglutamine diseases.

  46. Temporal regulation of Drosophila IAP1 determines caspase functions in sensory organ development Peer-reviewed

    Akiko Koto, Erina Kuranaga, Masayuki Miura

    JOURNAL OF CELL BIOLOGY　187　(2)　219-231　2009/10

    DOI： 10.1083/jcb.200905110 　

    ISSN： 0021-9525

  47. Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process Peer-reviewed

    Ayako Tonoki, Erina Kuranaga, Takeyasu Tomioka, Jun Hamazaki, Shigeo Murata, Keiji Tanaka, Masayuki Miura

    MOLECULAR AND CELLULAR BIOLOGY　29　(4)　1095-1106　2009/02

    DOI： 10.1128/MCB.01227-08 　

    ISSN： 0270-7306

  48. Non-classical caspase functions Peer-reviewed

    Erina Kuranaga, Masayuki Miura

    Seikagaku　80　(1)　24-28　2008

    Publisher: 1

    ISSN： 0037-1017

  49. DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells Peer-reviewed

    Paulo S. Ribeiro, Erina Kuranaga, Tencho Tenev, Francois Leulier, Masayuki Miura, Pascal Meier

    JOURNAL OF CELL BIOLOGY　179　(7)　1467-1480　2007/12

    DOI： 10.1083/jcb.200706027 　

    ISSN： 0021-9525

  50. Tumor suppressor CYLD regulates JNK-Induced cell death in Drosophila Peer-reviewed

    Lei Xue, Tatsushi Igaki, Erina Kuranaga, Hiroshi Kanda, Masayuki Miura, Tian Xu

    DEVELOPMENTAL CELL　13　(3)　446-454　2007/09

    DOI： 10.1016/j.devcel.2007.07.012 　

    ISSN： 1534-5807

  51. Local initiation of caspase activation in Drosophila salivary gland programmed cell death in vivo Peer-reviewed

    Kiwamu Takemoto, Erina Kuranaga, Ayako Tonoki, Takeharu Nagai, Atsushi Miyawaki, Masayuki Miura

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　104　(33)　13367-13372　2007/08

    DOI： 10.1073/pnas.0702733104 　

    ISSN： 0027-8424

  52. Nonapoptotic functions of caspases: caspases as regulatory molecules for immunity and cell-fate determination Peer-reviewed

    Erina Kuranaga, Masayuki Miura

    TRENDS IN CELL BIOLOGY　17　(3)　135-144　2007/03

    DOI： 10.1016/j.tcb.2007.01.001 　

    ISSN： 0962-8924

  53. Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs (vol 126, pg 583, 2006) Peer-reviewed

    Erina Kuranaga, Hirotaka Kanuka, Ayako Tonoki, Kiwamu Takemoto, Takeyasu Tomioka, Masatomo Kobayashi, Shigeo Hayashi, Masayuki Miura

    CELL　126　(4)　811-811　2006/08

    DOI： 10.1016/j.cell.2006.08.015 　

    ISSN： 0092-8674

  54. Drosophila IKK-related kinase regulates nonapoptotic function of caspases, via degradation of IAPs Peer-reviewed

    Erina Kuranaga, Hirotaka Kanuka, Ayako Tonoki, Kiwamu Takemoto, Takeyasu Tomioka, Masatomo Kobayashi, Shigeo Hayashi, Masayuki Miura

    CELL　126　(3)　583-596　2006/08

    DOI： 10.1016/j.cell.2006.05.048 　

    ISSN： 0092-8674

  55. IKK epsilon regulates F actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis Peer-reviewed

    Kenzi Oshima, Michiko Takeda, Erina Kuranaga, Ryu Ueda, Toshiro Aigaki, Masayuki Miura, Shigeo Hayashi

    CURRENT BIOLOGY　16　(15)　1531-1537　2006/08

    DOI： 10.1016/j.cub.2006.06.032 　

    ISSN： 0960-9822

  56. Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity

    Kanuka Hirotaka, Hiratou Tetsuo, Igaki Tatsushi, Kanda Hiroshi, Kuranaga Erina, Sawamoto Kazunobu, Aigaki Toshiro, Okano Hideyuki, Miura Masayuki

    Biochimica et Biophysica Acta - General Subjects　1726　(3)　225-237　2005/11/30

    DOI： 10.1016/j.bbagen.2005.06.020 　

    ISSN： 0304-4165

    More details Close

    <p>To elucidate the intrinsic mechanisms of neurotoxicity induction, including those underlying neural cell death and neurodegeneration, we developed a gain-of-function screen for gene products causing neural cell loss. To identify novel genes with a cell-death-related function in neurons, we screened 4,964 Drosophila GS lines, in which one or two genes from much of the Drosophila genome can be overexpressed. Approximately 0.68% of the GS lines produced phenotypes involving a loss of postmitotic neurons. Of these, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61α (DSec61α), an endoplasmic reticulum protein with protein translocation activity. Ectopic expression of DSec61α caused neural cell death accompanied by the accumulation of ubiquitinated proteins, which was mediated by DSec61α's translocon activity. This supported our previous observation that the DSec61α translocon contributes to expanded polyglutamine-mediated neuronal toxicity, which is also associated with ubiquitinated protein accumulation. These data suggest that the translocon may be a novel component of neural cell death and degeneration pathways. Our approach can be

  57. Gain-of-function screen identifies a role of the Sec61alpha translocon in Drosophila postmitotic neurotoxicity. Peer-reviewed

    Kanuka H, Hiratou T, Igaki T, Kanda H, Kuranaga E, Sawamoto K, Aigaki T, Okano H, Miura M

    Biochimica et biophysica acta　1726　225-237　2005/11/03

    Publisher: 3

    DOI： 10.1016/j.bbagen.2005.06.020 　

    ISSN： 0006-3002

  58. Drosophila caspase transduces Shaggy/GSK-3 beta kinase activity in neural precursor development Peer-reviewed

    H Kanuka, E Kuranaga, K Takemoto, T Hiratou, H Okano, M Miura

    EMBO JOURNAL　24　(21)　3793-3806　2005/11

    DOI： 10.1038/sj.emboj.7600822 　

    ISSN： 0261-4189

  59. Isolation of gene sets affected specifically by polyglutamine expression: implication of the TOR signaling pathway in neurodegeneration

    B Nelson, S Nishimura, H Kanuka, E Kuranaga, M Inoue, G Hori, H Nakahara, M Miura

    CELL DEATH AND DIFFERENTIATION　12　(8)　1115-1123　2005/08

    DOI： 10.1038/sj.cdd.4401635 　

    ISSN： 1350-9047

  60. Genetic approaches for the identification of apoptotic components Peer-reviewed

    Erina Kuranaga, Masayuki Miura

    Medical Molecular Morphology　38　(1)　18-22　2005

    Publisher: 1

    DOI： 10.1007/s00795-004-0276-x 　

    ISSN： 1860-1480 1860-1499

  61. Cytosol-endoplasmic reticulum interplay by Sec61 alpha translocon in polyglutamine-mediated neurotoxicity in Drosophila Peer-reviewed

    H Kanuka, E Kuranaga, T Hiratou, T Igaki, B Nelson, H Okano, M Miura

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　100　(20)　11723-11728　2003/09

    DOI： 10.1073/pnas.1934748100 　

    ISSN： 0027-8424

  62. Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila Peer-reviewed

    E Kuranaga, H Kanuka, T Igaki, K Sawamoto, H Ichijo, H Okano, M Miura

    NATURE CELL BIOLOGY　4　(9)　705-710　2002/09

    DOI： 10.1038/ncb842 　

    ISSN： 1465-7392

  63. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway Peer-reviewed

    T Igaki, H Kanda, Y Yamamoto-Goto, H Kanuka, E Kuranaga, T Aigaki, M Miura

    EMBO JOURNAL　21　(12)　3009-3018　2002/06

    DOI： 10.1093/emboj/cdf306 　

    ISSN： 0261-4189

  64. Requirement of the Fas ligand-expressing luteal immune cells for regression of corpus luteum Peer-reviewed

    E Kuranaga, H Kanuka, Y Furuhata, T Yonezawa, M Suzuki, M Nishihara, R Takahashi

    FEBS LETTERS　472　(1)　137-142　2000/04

    DOI： 10.1016/S0014-5793(00)01426-5 　

    ISSN： 0014-5793

  65. Suppression of copulatory behavior by intracerebroventricular infusion of antisense oligodeoxynucleotide of granulin in neonatal male rats Peer-reviewed

    Masatoshi Suzuki, Makoto Bannai, Mie Matsumuro, Yasufumi Furuhata, Ryota Ikemura, Erina Kuranaga, Yasufumi Kaneda, Masugi Nishihara, Michio Takahashi

    Physiology and Behavior　68　(5)　707-713　2000

    Publisher: Elsevier Inc.

    DOI： 10.1016/S0031-9384(99)00241-3 　

    ISSN： 0031-9384

  66. Progesterone is a cell death suppressor that downregulates Fas expression in rat corpus luteum Peer-reviewed

    E Kuranaga, H Kanuka, K Hirabayashi, M Suzuki, M Nishihara, M Takahashi

    FEBS LETTERS　466　(2-3)　279-282　2000/01

    ISSN： 0014-5793

  67. Fas/Fas ligand system in prolactin-induced apoptosis in rat corpus luteum: Possible role of luteal immune cells Peer-reviewed

    E Kuranaga, H Kanuka, M Bannai, M Suzuki, M Nishihara, M Takahashi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　260　(1)　167-173　1999/06

    ISSN： 0006-291X

Show all ︎Show first 5

Misc. 23

  1. The role of endocytosis for epidermal tissue remodeling during insect metamorphosis

    梅津大輝, 倉永英里奈

    医学のあゆみ　274　(5)　2020

    ISSN： 0039-2359

  2. Wave propagation of junctional remodeling in collective cell movement of epithelial tissue

    Tetsuya Hiraiwa, Erina Kuranaga, Tatsuo Shibata

    MECHANISMS OF DEVELOPMENT　145　S41-S41　2017/07

    DOI： 10.1016/j.mod.2017.04.063 　

    ISSN： 0925-4773

    eISSN： 1872-6356

  3. In vivo and in silico analyses reveal a novel mechanism for directional collective cell migration in epithelial morphogenesis

    67　(2)　163-167　2016/03

    Publisher: 金原一郎記念医学医療振興財団 ; 1949-

    ISSN： 0370-9531

  4. Active participation of cell death during epithelial morphogenesis

    246　(5)　385-391　2013/08/03

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  5. TDP-43トランスジェニックショウジョウバエにおける神経変性機序の解析

    井原 涼子, 辻 省次, 倉永 英里奈, 三浦 正幸, 長田 有生, 橋本 唯史, 田中 啓祥, 若林 朋子, 岩坪 威

    臨床神経学　51　(12)　1273-1273　2011/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  6. Inflammatory response and tissue regeneration in Drosophila

    62　(3)　249-256　2011/05

    Publisher: 金原一郎記念医学医療振興財団

    ISSN： 0370-9531

  7. ショウジョウバエを用いたプロテアソーム遺伝学的相互作用因子の探索

    上地 浩之, 濱崎 純, 倉永 英里奈, 三浦 正幸, 村田 茂穂

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　4P-0570　2010/12

    Publisher: (公社)日本生化学会

  8. TDP-43トランスジェニックショウジョウバエにおける神経変性機序の解析

    井原 涼子, 辻 省次, 倉永 英里奈, 三浦 正幸, 長田 有生, 橋本 唯史, 田中 啓祥, 若林 朋子, 岩坪 威

    臨床神経学　50　(12)　1199-1199　2010/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  9. Programmed cell death controls spacing pattern of Drosophila sensory bristles

    A. Koto, E. Kuranaga, M. Miura

    DIFFERENTIATION　80　S48-S49　2010/11

    DOI： 10.1016/j.diff.2010.09.100 　

    ISSN： 0301-4681

  10. Apoptosis drives collective cell movement that is required for the morphogenesis of Drosophila male terminalia

    E. Kuranaga, M. Miura

    DIFFERENTIATION　80　S52-S52　2010/11

    DOI： 10.1016/j.diff.2010.09.110 　

    ISSN： 0301-4681

  11. Apoptosis controls the speed of looping morphogenesis in Drosophila male terminalia

    Erina Kuranaga, Masayuki Miura

    DEVELOPMENTAL BIOLOGY　344　(1)　419-419　2010/08

    DOI： 10.1016/j.ydbio.2010.05.044 　

    ISSN： 0012-1606

  12. S2-03 生体イメージングにより解析する器官形成における細胞死の役割(S2 発生・再生医学における先端研究の展開,シンポジウム,第50回日本組織細胞化学会総会・学術集会)

    倉永英里奈, 三浦正幸

    日本組織細胞化学会総会プログラムおよび抄録集　(50)　48-48　2009/09/26

    Publisher: 日本組織細胞化学会

  13. 神経変性疾患関連遺伝子探索と機能解析 晩発性神経変性疾患における26Sプロテアソームの関与

    殿城 亜矢子, 倉永 英里奈, 富岡 武泰, 濱崎 純, 村田 茂穂, 田中 啓二, 三浦 正幸

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　81回・31回　3S25-6　2008/11

    Publisher: (公社)日本生化学会

  14. RNA-binding protein hoip accelerates polyQ-induced neurodegeneration in Drosophila

    Takuya Murata, Eriko Suzuki, Saya Ito, Shun Sawatsubashi, Yue Zhao, Kaoru Yamagata, Masahiko Tanabe, Sally Fujiyama, Shuhei Kimura, Takashi Ueda, Hiroyuki Matsukawa, Alexander Kouzmenko, Takashi Furutani, Erina Kuranaga, Masayuki Miura, Ken-ichi Takeyama, Shigeaki Kato

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY　72　(9)　2255-2261　2008/09

    DOI： 10.1271/bbb.70829 　

    ISSN： 0916-8451

    eISSN： 1347-6947

  15. Sensing and reacting to dangers by caspases: Caspase activation via inflammasomes

    Asuka Takeishi, Erina Kuranaga, Masayuki Miura

    DRUG DISCOVERIES AND THERAPEUTICS　2　(1)　14-23　2008/02

    ISSN： 1881-7831

    eISSN： 1881-784X

  16. Non-classical caspase functions

    KURANAGA Erina, MIURA Masayuki

    80　(1)　24-28　2008/01/25

    Publisher: 日本生化学会

    ISSN： 0037-1017

  17. Non-classical caspase functions and its regulatory mechanisms

    Protein, nucleic acid and enzyme　52　(11)　1337-1343　2007/09

    Publisher: 共立出版

    ISSN： 0039-9450

  18. 細胞を殺さない,カスパーゼの新機能 (特集 細胞死の生物学--アポトーシスシグナルからみえてきた新しい生理機能)

    倉永 英里奈, 三浦 正幸

    バイオニクス　4　(3)　44-48　2007/03

    Publisher: オーム社

    ISSN： 1349-9343

  19. Genetic analysis for JNK-mediated apoptosis

    E Kuranaga, M Miura

    ACTA HISTOCHEMICA ET CYTOCHEMICA　37　(4)　223-226　2004

    ISSN： 0044-5991

    eISSN： 1347-5800

  20. W4-3 JNKを介した細胞死の遺伝学的解析(アポトーシスの基礎から臨床まで,ワークショップ4,第44回日本組織細胞化学会 第35回日本臨床電子顕微鏡学会 合同学術集会)

    倉永英里奈, 三浦正幸

    日本組織細胞化学会総会プログラムおよび抄録集　(44)　50-50　2003/10/29

    Publisher: 日本組織細胞化学会

  21. Molecular genetic control of caspases and JNK-mediated neural cell death

    E Kuranaga, M Miura

    ARCHIVES OF HISTOLOGY AND CYTOLOGY　65　(4)　291-300　2002/10

    ISSN： 0914-9465

    eISSN： 1349-1717

  22. Cell death execution mechanisms in Drosophila.

    Kanda H, Igaki T, Kuranaga E, Kanuka H, Miura M

    RIKEN Review　41　33-34　2001

  23. カスパーゼ活性化の調節遺伝子群--ショウジョウバエからの新展開 (特集 細胞の生と死の制御機構の多様性)

    倉永 英里奈, 嘉糠 洋陸, 三浦 正幸

    モレキュラ-メディシン　37　(4)　398-407　2000/04

    Publisher: 中山書店

    ISSN： 0918-6557

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Research Projects 20

  1. Elucidation of the mechanistical principle of collective cell migration in individuals

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    Institution: Kyoto University

    2024/04/01 - 2028/03/31

  2. Cross-Scale Intracellular Molecular Structural Dynamics Reveals Mechanisms of Body Axis Formation and Homeostasis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Transformative Research Areas (A)

    Institution: Tohoku University

    2021/09/10 - 2026/03/31

  3. Cross-scale biology

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Transformative Research Areas (A)

    Institution: The University of Tokyo

    2021/09/10 - 2026/03/31

  4. Development of a new renal therapy through Gut-renal axis

    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

    2021/04/01 - 2024/03/31

  5. Screen for metabolic pathways and nutrients that inhibit neurodegeneration

    Kuranaga Erina

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2017/06/30 - 2020/03/31

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    In this study, we aim to control the nutrient intake and its metabolites in order to reduce the onset and pathogenesis of neurodegenerative diseases. The aim of the study was to explore the mechanisms that can inhibit progression of the disease. We found that activation of the ubiquitin-proteasome system reduces symptoms in neurodegenerative disease systems. Confirmation. We screened for nutritional factors and drugs using life span extension as an indicator in neurodegenerative disease strains. Since glucose metabolism was assumed to be involved in the changes in lifespan, we screened for drugs that increase ATP production.The effectiveness of the drugs was examined using the following methods. The results showed that drugs that maintain ATP production were effective. We are planning to elucidate the action of these results in the future.

  6. Principle of collective cell migration to construct multicellular systems

    Kuranaga Erina

    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

    2016/04/01 - 2019/03/31

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    During the formation of the body from a fertilized egg, epithelial cells migrate collectively in the same direction to create a complex organism. However, how epithelial cells can migrate while maintaining cell-to-cell adhesion remains largely a mystery. To understand this mechanism, we focused on the looping morphogenesis of the male genitalia (genitalia rotation) during the Drosophila pupal stage. This genitalia rotation occurs when individual epithelial cells are interchanged asymmetrically and migrate collectively. In the present study, we found that actomyosin, which is localized on the cell adhesion and causes junction remodeling (contraction of the cell adhesion), contributes to the elongation of the newly formed cell adhesion surface on both sides of the dissociated cell. In addition, we show that sidekick, a localized protein of tri-cellular junction (three cell adhesion bond), is involved in this phenomenon.

  7. International netoworking on cell competition for the next generation

    Fujita Yasuyuki, Tada Masazumi, Levayer Romain, Dahmann Christian, Toyama Yusuke, Hyman Anthony, Yan Yan, Bach Erika, Vittelo Elisa, Elleni Bali

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Hokkaido University

    2015/11/06 - 2019/03/31

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    We organized 2nd (Madrid) and 3rd (Sapporo) Cell Competition International Symposium, and UK-Japan symposium on cell competition (London) to present our research achievement to foreign scientists and to provoke international collaboration with the attendees. In addition, to facilitate international collaborations on cell competition, a number of young Japanese scientists have sent to several research institutes in forein countries. Moreover, several outstanding cell competition experts or young scientists have been invited to come over to Japan.

  8. Identification of cell competition mediators that maintain barrier function of epidermis

    Kuranaga Erina, Umetsu Daiki, Uechi Hiroyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    2014/07/10 - 2019/03/31

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    In this study, we considered the process of epithelial cell remodeling in Drosophila during metamorphosis as an example of physiological cell competition, and searched for factors that induce non-autonomous cell death by using genetic screening. Pvf1, a Drosophila homolog of vascular endothelial growth factor, was identified as a factor on the winner cell side. As a loser-side factor, myosin VI involved in vesicle transport endocytosis was identified. In addition, we also analyzed cell competition-like phenomena in other epithelial cell populations. We established an experimental material that enables analysis of cell competition in epithelial rearrangement and published it.

  9. Cell competition: a mechanism for survival of the fittest in the multi-cellular community

    Fujita Yasuyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Hokkaido University

    2014/07/10 - 2019/03/31

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    We organized 1st, 2nd, 3rd Cell Competition International Symposium in 2015 (Kyoto), 2016 (Madrid) and 2017 (Sapporo), respectively. Also we held general meeting for this reseach area, and 'Cell Competition colloquium’ to boost education for young scientists. In addition, to facilitate research collaboration between young scientists, we set up specific research funding and support 6 pairs of intra-area collaborations. Furtheremore, by technical support center organized by 6 main researchers, we support the research and collborative studies within the area.

  10. in vivo analysis of collective cell movement

    Kuranaga Erina

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (A)

    2012/04/01 - 2017/03/31

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    Morphogenetic epithelial movement occurs during embryogenesis and drives complex tissue formation. However, how epithelial cells coordinate their unidirectional movement while maintaining epithelial integrity is unclear. Here we propose a novel mechanism for collective epithelial cell movement based on Drosophila genitalia rotation, in which epithelial tissue rotates clockwise around the genitalia. We found that the moving cells exhibited repeated left-right-biased junction remodeling, while maintaining adhesion with their neighbors, in association with a polarized myosin II distribution. Numerical simulations revealed that a left-right asymmetry in cell intercalation was sufficient to induce unidirectional cellular movement. These findings support a model in which left-right asymmetric cell intercalation within an epithelial sheet drives collective cellular movement in the same direction.

  11. Genetic analysis of the systemic damage response via caspase pathway to maintain homeostasis

    KURANAGA Erina

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    2009/07/23 - 2014/03/31

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    In this study, we focused on stress responses and metabolic alterations in the Drosophila apaf-1 (dpf-1) mutant, in which caspase activation and subsequent apoptosis are severely impaired. The dpf-1 mutant was found to be sensitive to injury- and starvation-stress. We show that dpf-1 mutant has defects in homeostatic gut cell renewal and that inhibiting caspase activity in fly enterocytes results in the production of systemic lethal factors after wounding. We then conducted metabolomic analyses of the hemolymph in dpf-1 mutants to investigate the physiological consequences of caspase inhibition. Several metabolites were found at higher levels in dpf-1 mutants than in wild type, which for at least one of the metabolites, was likely due to alteration of expression levels of putative metabolic enzymes in the fat body. Together, these results suggest caspase activity is required in the gut to regulate the systemic defense response in order to overcome stress in vivo.

  12. Homeostatic inflammation: Molecular basis and dysregulation

    MIYAKE Kensuke, KAISHO Tsuneyasu, MUTA Tatsushi, KURATA Shoichiro, KURANAGA Erina, OGAWA Yoshihiro, MARU Yoshiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: The University of Tokyo

    2009/07/23 - 2014/03/31

  13. In vivo imaging analysis for cellular and molecular mechanisms of body axis tuning

    KURANAGA Erina

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (A)

    2009 - 2011

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    In Drosophila development, male genitalia performs 360o clockwise rotation as it forms, but L/R axis of genitalia is deformed if the rotation is incompletely stopped. Imaging analysis reveals that full rotation of genitalia is required the two steps movement of collective cells in epithelial sheet surrounding genitalia. We found that the secondary rotation that was initiated by apoptosis accelerated the primary rotation to adjust the speed of morphogenesis for the developmental time window.

  14. 生体レベルにおけるカスパーゼ生理機能とその制御メカニズムの遺伝学的解析

    倉永 英里奈, 三浦 正幸

    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: 東京大学

    2009 - 2009

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    カスパーゼは細胞死のメディエーターとして機能するシステインプロテアーゼであり、線虫からほ乳類まで保存されている。しかしながらその後の研究から、カスパーゼは細胞死実行のみならず、細胞分化、増殖、移動および炎症性サイトカインの放出といったさまざまな生理現象にも関与していることが明らかとなってきた。我々はこれまでに、細胞死以外の細胞機能に関与するカスパーゼ活性調節因子をスクリーニングにより同定した。この解析の中で我々は、FRET型のカスパーゼ活性インディケーター(SCAT)を用いて、個体レベル・単一細胞レベルでの段階的カスパーゼ活性を検出する方法を確立した。以降、生体レベルにおけるカスパーゼの生理機能を、このSCATを用いて解析している。今年度の本研究において特に注目したカスパーゼの生理機能は、周辺細胞に対する代償性増殖因子の放出である。死ぬ細胞が組織の中で自分の消失した間隙を埋めるように周りの細胞に対して増殖因子を分泌すると考えられ、「代償性増殖」として位置づけられている。この代償性増殖を誘導する細胞死シグナルの一つとしてショウジョウバエcaspase-9が、当研究室を含めた研究グループから報告された。代償性増殖因子は死ぬ細胞から放出されるため、死ぬ細胞が死なずに停滞する、または除去されない場合には、周りの細胞に過剰な増殖がみられるため、がん化のリスクを上昇させてしまうであろう。平成19年度に行った研究において、我々はショウジョウバエcaspase-9の活性を検出するSCATプローブを作製し、代償性増殖を誘導した組織において、caspase-9の強い活性上昇を検出した(未発表)。また、caspase-9による代償性増殖過剰モデルを用いて、RNAiクリーニング行い、過剰増殖を抑制する系統を複数得た。候補タンパク質がcaspase-9によって切断されることを、培養細胞を用いた実験により確認し、基質としてin vivoでどのような生理機能を発揮するか、さらなる解析が必要である。

  15. 生体レベルにおけるカスパーゼ生理機能を制御する基質の遺伝学的解析

    倉永 英里奈, 三浦 正幸

    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: 東京大学

    2007 - 2008

    More details Close

    カスパーゼは細胞死のメディエーターとして機能するシステインプロテアーゼであり、線虫からほ乳類まで保存されている。しかしながらその後の研究から、カスパーゼは細胞死実行のみならず、細胞分化、増殖、移動および炎症性サイトカインの放出といったさまざまな生理現象にも関与していることが明らかとなってきた。我々はこれまでに、細胞死以外の細胞機能に関与するカスパーゼ活性調節因子をスクリーニングにより同定した。この解析の中で我々は、FRET型のカスパーゼ活性インディケーター(SCAT)を用いて、個体レベル・単一細胞レベルでの段階的カスパーゼ活性を検出する方法を確立した。以降、生体レベルにおけるカスパーゼの生理機能を、このSCATを用いて解析している。今年度の本研究において特に注目したカスパーゼの生理機能は、周辺細胞に対する代償性増殖因子の放出である。死ぬ細胞が組織の中で自分の消失した間隙を埋めるように周りの細胞に対して増殖因子を分泌すると考え照れ、「代償性増殖」として位置づけられている。この代償性増殖を誘導する細胞死シグナルの一つとしてショウジョウバエcaspase-9が、当研究室を含めた研究グループから報告された。代償性増殖因子は死ぬ細胞から放出されるため、死ぬ細胞が死なずに停滞する、または除去されない場合には、周りの細胞に過剰な増殖がみられるため、がん化のリスクを上昇させてしまうであろう。平成19年度に行った研究において、我々はショウジョウバエcaspase-9の活性を検出するSCATプローブを作製し、代償性増殖を誘導した組織において、caspase-9の強い活性上昇を検出した(未発表)。また、caspase-9による代償性増殖過剰モデルを用いて、RNAiクリーニング行い、過剰増殖を抑制する系統を複数得た。候補タンパク質がcaspase-9によって切断されることを、培養細胞を用いた実験により確認し、基質としてin vivoでどのような生理機能を発揮するか、さらなる解析を行っていく。

  16. カスパーゼによる生体防御シグナルの遺伝学的解析

    倉永 英里奈, 三浦 正幸

    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: 東京大学

    2007 - 2008

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    カスパーゼは細胞死のメディエーターとして機能するシステインプロテアーゼであり、生体防御機構においても重要な役割を担うことが知られている。カスパーゼ1や11はマクロファージなどの免疫系細胞において炎症性サイトカインの分泌に関与し、同時にカスパーゼはイニシエーターカスパーゼとして細胞死実行カスパーゼであるカスパーゼ3を活性化する。しかしながら、生体防御反応時においていつ、どこでカスパーゼが活性化するのか未だ明らかでない。そこで、カスパーゼの活性化を可視化するツールとして、FRETを用いたインディケーター(SCAT3)を発現するショウジョウバエ系統を作製した。ショウジョウバエの脂肪体は感染時に抗菌ペプチドを産生する器官として知られている。我々は、ショウジョウバエの遺伝学的手法を用いてショウジョウバエの脂肪体にSCAT3を発現させ、感染後のカスパーゼ活性検出を試みた。ショウジョウバエ腹部にE. coliをマイクロインジェクションした後に、時間経過毎に脂肪体を取り出し、単一細胞レベルでのカスパーゼ活性を観察した。その結果、E. coliの注入後30分の間において、脂肪体細胞の一部の細胞で、細胞死を誘導するのに十分なカスパーゼ活性が観察された。感染後の免疫担当細胞におけるカスパーゼ活性化動態の単一細胞レベルでの観察はこれまでに報告が無く、新しい知見である。興味深いことに、カスパーゼ活性が観察されたのは一部の細胞だけではなく、それ以外の細胞においても、微弱な、あるいは一時的なカスパーゼ活性が検出された。この活性が、持続し細胞死を誘導するものかどうかについて、E. coli注入後6時間の脂肪体細胞を観察したところ、活性化が見られなかったことから、感染後初期に誘導された一時的な活性化であることが考えられ、E. coliの感染初期においてカスパーゼが何らかの生理機能を果たしていることが示唆された。

  17. 雄性外生殖器における形態形成の制御メカニズム

    倉永 英里奈, 三浦 正幸

    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: 東京大学

    2007 - 2008

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    我々は、発生過程に関与する細胞死に着目し、細胞死シグナルの生理的な機能を探索するためにショウジョウバエカスパーゼ変異体を作成し、その細部にわたる解析を行った。その過程で雄性外生殖器の形成不全が観察されたことから、この研究課題において「外生殖器形成不全を規定する遺伝子の同定」及び、「生殖器形成に関わるカスパーゼシグナルとその制御機構の探索」を基幹実験テーマに据え、性分化メカニズムの-端を明らかにすることを目指している。ショウジョウバエの雄性外生殖器は、器官形成過程においてほ乳類の心臓などと同様に左右非対称に回転することが知られており、この回転が不完全だと外生殖器の形態が異常になり、雄性不妊となる。そこで本研究課題において、生きた個体を用いた生殖腺形態形成のイメージング解析法を確立して観察を行った。その結果、外生殖器の周りを取り囲む細胞が、集団で同一方向に移動していることで回転を制御している様子が観察された。一方、移動している細胞のさらに周囲を取り囲む細胞層では、細胞の移動は観られず、一部の細胞が死んでいることが明らかとなった。この細胞死を抑制することで回転異常を示すことから、外生殖器の器官形成における細胞移動と細胞死の相関が示唆された。細胞死の回転への寄与を定量化するために、正常な個体と細胞死を抑制した個体で回転のスピードを比較したところ、正常な個体において観られる回転速度の上日が、細胞死を抑制した個体では観察されず、一定の速度で回転して正常な個体と同じ時間経過で停止してしまった。この結果から、細胞死は発生の一定時間内に外生殖器の形態形成を完了するために重要な役割を持つことが示唆された(投稿準備中)。

  18. 神経変性・細胞死を抑制するプロテアソーム活性化因子の遺伝学的解析

    倉永 英里奈

    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)

    Institution: 東京大学

    2005 - 2007

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    多くの神経変性疾患において、細胞内の異常タンパク質の凝集・蓄積とそれに伴う神経細胞死が共通する病態としで知られている。通常細胞内の異常タンパク質は、タンパク質分解機構の一つであるユビキチンプロテアソームシステム(UPS)によって分解され細胞内の恒常性が維持されているが、UPSが正常に働かない場合、細胞内の異常タンパク質は凝集体を形成して神経変性や神経細胞死を引き起こすことが明らかになりつつある。しかしながら、実際にプロテアソーム活性の変化と神経変性疾患の関与に関して、in vivoで解析を行った研究はこれまでに少ない。我々は、ショウジョウバエをモデル生物として用いて、in vivoにおける神経変性とプロテアソーム活性の関与を示すことを試みた。これまでに行った神経変性抑制因子の過剰発現型スクリーニングにより、DANC系統を同定した。DANC系統による抑制型表現系の原因を特定するために、DANC系統がコードする遺伝子の探索を行ったところ、その候補に26Sプロテアソームの構成因子であるRpn11が同定された。DANC系統ではRpn11の過剰発現により、神経変性の抑制表現型が得られたと考えられる。Rpn11がプロテアソーム構成因子であることからプロテアソーム活性に着目し、ショウジョウバエ個体におけるプロテアソーム活性を測定したところ、DANC系統及びRpn11発現系統において恒常的にプロテアソーム活性が上昇しているという結果を得た。また、ショウジョウバエにおいてRpn11遺伝子のノックダウンを行ったところ、プロテアソーム活性の減少・神経変性様表現系の表出が確認されたことから、in vivoにおける神経変性とプロテアソーム活性の変化が密接に関係していることが示唆された。本研究の成果は、現在投稿準備中である。

  19. 細胞死シグナルによる外部生殖機形成機構の遺伝学的解析

    倉永 英里奈, 三浦 正幸

    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: 東京大学

    2005 - 2006

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    多くの生物において、プログラム細胞死は組織形成の課程で広範に認められ、体内のホメオスタシスの維持においても重要な役割を果たすと考えられる。我々はショウジョウバエをモデルとして細胞死のシグナル経路を解析してきたが、我々を含む複数のグループによって細胞死実行プロテアーゼであるカスパーゼ活性と雄性外生殖器の形態形成との相関が見出されてきた。ショウジョウバエの雄性外生殖器は、雄の体内で観察される直腸を360度取り囲むように配置される射精管の形態から、その形成時に回転することが発生の重要なステップとされているが、カスパーゼ阻害による雄性外生殖雛の形成不全はこの段階においての回転が不完全となってしまうと考えられた。本研究において我々は、蛹期における雄性生殖器め回転をen-GAL4/UAS-bCD8-GFP系統のハエを観察することでイメージングすることに成功した。生殖器の回転は、カスパーゼ阻害剤のp35を発現させた系統(en-GAL4/UAS-bCD8-GFP UAS-p35)で途中停止したことから、カスパーゼが雄性生殖器と内部後腸の正常配置の制御に関与している可能性が考えられた。蛍光タンパク質を用いたFRET(蛍光共鳴エネルギー移動)を利用して作製したカスパーゼ活性化のインディケーター(SCAT)を発現するトランスジェニックショウジョウバエを作製し、雄性外生殖器形成課程のラィブィメージングを行った。その結果、回転時またはその前後においてカスパーゼの活性化は、回転している外生殖器原器を取り囲む細胞で観察された。最近我々は、微弱なカスパーゼ活性が細胞死ではなく細胞運動や細胞分化を制御することを明らかにした。今後細胞死シグナルが、回転する課程での周辺上皮細胞の津動を制御する可能性について検討したい。

  20. 神経細胞死を抑制するプロテアソーム活性化因子の遺伝学的解析

    倉永 英里奈, 三浦 正幸

    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: 東京大学

    2005 - 2006

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    多くの神経変性疾患において、細胞内の異常タンパク質の凝集・蓄積とそれに伴う神経細胞死が共通する病態として知られている。通常細胞内の異常タンパク質は、タンパク質分解機構の一つであるユビキチンプロテアソームシステム(UPS)によって分解され細胞内の恒常性が維持されているが、UPSが正常に働かない場合、細胞内の異常タンパク質は凝集体を形成して神経変性や神経細胞死を引き起こすことが明らかになりつつある。しかしながら、実際にプロテアソーム活性の変化と神経変性疾患の関与に関して、in vivoで解析を行った研究はこれまでに少ない。私たちは、ショウジョウバエをモデル生物として用いて、in vivoにおける神経変性とプロテアソーム活性の関与を示すことを試みた。まず、神経変性が晩発性に発症する原因として加齢依存的なプロテアソーム活性の変化を想定し、ショウジョウバエ頭部のプロテアソーム活性を測定した。その結果、若年個体と比較して老齢個体におけるプロテアソーム活性の段階的な低下が槻察された。プロテアソーム活性の老齢個体における低下または若年個体での亢進が何によって制御されているのか、遺伝学的なスクリーニングにより制御分子の同定を目指している。また、これまでに行った神経変性抑制因子の過剰発現型スクリーニングにより、DANC系統を同定した。DANC系統による抑制型表現系の原因を特定するために、DANC系統がコードする遺伝子の探索を行ったところ、その候補に26Sプロテアソームの構成因子であるRpnが同定された。DANC系統ではRpnの過剰発現により、神経変性の抑制表現型が得られたと考えられる。Rpnがプロテアソーム構成因子であることからプロテアソーム活性に着目し、ショウジョウバエ個体におけるプロテアソーム活性を測定したところ、DANC系統及びRpn発現系統において恒常的にプロテアソーム活性が上昇しているという結果を得た。また、ショウジョウバエにおいてRpn遺伝子のノックダウンを行ったところ、プロテアソーム活性の減少・神経変性様表現系の表出が確認されたことから、in vivoにおける神経変性とプロテアソーム活性の変化が密接に関係していることが示唆された。

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