研究者業績

八杉 徹雄

Tetsuo Yasugi

基本情報

所属
上智大学 理工学部 物質生命理工学科 准教授
学位
博士(理学)(東京大学大学院)

研究者番号
90508110
J-GLOBAL ID
201801006513941583
researchmap会員ID
B000303879

論文

 24
  • 田中 吉太郎, 八杉 徹雄
    応用数理 33(2) 72-82 2023年6月  査読有り招待有り
  • Tetsuo Yasugi, Makoto Sato
    Fly 16(1) 24-36 2022年12月  
    Notch signalling is a well-conserved signalling pathway that regulates cell fate through cell-cell communication. A typical feature of Notch signalling is 'lateral inhibition', whereby two neighbouring cells of equivalent state of differentiation acquire different cell fates. Recently, mathematical and computational approaches have addressed the Notch dynamics in Drosophila neural development. Typical examples of lateral inhibition are observed in the specification of neural stem cells in the embryo and sensory organ precursors in the thorax. In eye disc development, Notch signalling cooperates with other signalling pathways to define the evenly spaced positioning of the photoreceptor cells. The interplay between Notch and epidermal growth factor receptor signalling regulates the timing of neural stem cell differentiation in the optic lobe. In this review, we summarize the theoretical studies that have been conducted to elucidate the Notch dynamics in these systems and discuss the advantages of combining mathematical models with biological experiments.
  • Shin-Ichiro Ei, Hiroshi Ishii, Makoto Sato, Yoshitaro Tanaka, Miaoxing Wang, Tetsuo Yasugi
    Journal of Mathematical Biology 82(6) 2021年5月1日  
    The original version of this article unfortunately contained a mistake in Fig. 1b. The corrected Fig. 1b is given below.
  • Miaoxing Wang, Xujun Han, Chuyan Liu, Rie Takayama, Tetsuo Yasugi, Shin-Ichiro Ei, Masaharu Nagayama, Yoshitaro Tanaka, Makoto Sato
    Nature communications 12(1) 2083-2083 2021年4月7日  
    While Delta non-autonomously activates Notch in neighboring cells, it autonomously inactivates Notch through cis-inhibition, the molecular mechanism and biological roles of which remain elusive. The wave of differentiation in the Drosophila brain, the 'proneural wave', is an excellent model for studying Notch signaling in vivo. Here, we show that strong nonlinearity in cis-inhibition reproduces the second peak of Notch activity behind the proneural wave in silico. Based on this, we demonstrate that Delta expression induces a quick degradation of Notch in late endosomes and the formation of the twin peaks of Notch activity in vivo. Indeed, the amount of Notch is upregulated and the twin peaks are fused forming a single peak when the function of Delta or late endosomes is compromised. Additionally, we show that the second Notch peak behind the wavefront controls neurogenesis. Thus, intracellular trafficking of Notch orchestrates the temporal dynamics of Notch activity and the temporal patterning of neurogenesis.
  • Shin-Ichiro Ei, Hiroshi Ishii, Makoto Sato, Yoshitaro Tanaka, Miaoxing Wang, Tetsuo Yasugi
    Journal of mathematical biology 2020年9月21日  査読有り
    In this paper, we introduce a continuation method for the spatially discretized models, while conserving the size and shape of the cells and lattices. This proposed method is realized using the shift operators and nonlocal operators of convolution types. Through this method and using the shift operator, the nonlinear spatially discretized model on the uniform and nonuniform lattices can be systematically converted into a spatially continuous model; this renders both models point-wisely equivalent. Moreover, by the convolution with suitable kernels, we mollify the shift operator and approximate the spatially discretized models using the nonlocal evolution equations, rendering suitable for the application in both experimental and mathematical analyses. We also demonstrate that this approximation is supported by the singular limit analysis, and that the information of the lattice and cells is expressed in the shift and nonlocal operators. The continuous models designed using our method can successfully replicate the patterns corresponding to those of the original spatially discretized models obtained from the numerical simulations. Furthermore, from the observations of the isotropy of the Delta-Notch signaling system in a developing real fly brain, we propose a radially symmetric kernel for averaging the cell shape using our continuation method. We also apply our method for cell division and proliferation to spatially discretized models of the differentiation wave and describe the discrete models on the sphere surface. Finally, we demonstrate an application of our method in the linear stability analysis of the planar cell polarity model.
  • Min Zhang, Kaz Nagaosa, Yuji Nakai, Tetsuo Yasugi, Masako Kushihiki, Dini Rahmatika, Makoto Sato, Akiko Shiratsuchi, Yoshinobu Nakanishi
    Genes to cells : devoted to molecular & cellular mechanisms 2020年8月31日  査読有り
    Immunity is considered to be involved in the prevention of cancer. Although both humoral and cellular immune reactions may participate, underlying mechanisms have yet to be clarified. The present study was conducted to clarify this issue using a Drosophila model, in which neoplastic transformation was induced through the simultaneous inhibition of cell-cycle checkpoints and apoptosis. We first determined the location of hemocytes, blood cells of Drosophila playing a role of immune cells, in neoplasia-induced and normal larvae, but there was no significant difference between the two groups. When gene expression pattern in larval hemocytes was determined, the expression of immunity-related genes including those necessary for phagocytosis was reduced in the neoplasia model. We then asked the involvement of phagocytosis in the prevention of neoplasia examining animals where the expression of engulfment receptors instead of apoptosis was retarded. We found that the inhibition of engulfment receptor expression augmented the occurrence of neoplasia induced by a defect in cell-cycle checkpoints. This suggested a role for phagocytosis in the prevention of neoplastic transformation in Drosophila.
  • Chuyan Liu, Olena Trush, Xujun Han, Miaoxing Wang, Rie Takayama, Tetsuo Yasugi, Takashi Hayashi, Makoto Sato
    Nature communications 11(1) 4067-4067 2020年8月13日  査読有り
    The brain is organized morphologically and functionally into a columnar structure. According to the radial unit hypothesis, neurons from the same lineage form a radial unit that contributes to column formation. However, the molecular mechanisms that link neuronal lineage and column formation remain elusive. Here, we show that neurons from the same lineage project to different columns under control of Down syndrome cell adhesion molecule (Dscam) in the fly brain. Dscam1 is temporally expressed in newly born neuroblasts and is inherited by their daughter neurons. The transient transcription of Dscam1 in neuroblasts enables the expression of the same Dscam1 splice isoform within cells of the same lineage, causing lineage-dependent repulsion. In the absence of Dscam1 function, neurons from the same lineage project to the same column. When the splice diversity of Dscam1 is reduced, column formation is significantly compromised. Thus, Dscam1 controls column formation through lineage-dependent repulsion.
  • Makoto Sato, Tetsuo Yasugi
    Advances in experimental medicine and biology 1218 77-91 2020年  査読有り
    Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt-and-pepper pattern formation during various biological processes. In many cases, Notch signaling acts together with other signaling systems. However, it is not clear what happens when Notch signaling is combined with other signaling systems. Mathematical modeling and the use of a simple biological model system will be essential to address this uncertainty. A wave of differentiation in the Drosophila visual center, the "proneural wave," accompanies the activity of the Notch and EGF signaling pathways. Although all of the Notch signaling components required for lateral inhibition are involved in the proneural wave, no salt-and-pepper pattern is found during the progression of the proneural wave. Instead, Notch is activated along the wave front and regulates proneural wave progression. How does Notch signaling control wave propagation without forming a salt-and-pepper pattern? A mathematical model of the proneural wave, based on biological evidence, has demonstrated that Notch-mediated lateral inhibition is implemented within the proneural wave and that the diffusible action of EGF cancels salt-and-pepper pattern formation. The results from numerical simulation have been confirmed by genetic experiments in vivo and suggest that the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a novel function of Notch signaling that regulates propagation of the proneural wave. Similar mechanisms may play important roles in diverse biological processes found in animal development and cancer pathogenesis.
  • Suzuki T, Liu C, Kato S, Nishimura K, Takechi H, Yasugi T, Takayama R, Hakeda-Suzuki S, Suzuki T, Sato M
    iScience 8 148-160 2018年9月  査読有り
  • Sato M, Yasugi T, Trush O
    Neuroscience research 2018年9月  査読有り
  • Tanaka Y, Yasugi T, Nagayama M, Sato M, Ei SI
    Scientific reports 8(1) 12484 2018年8月  査読有り
  • Makoto Sato, Tetsuo Yasugi, Yoshitaro Tanaka, Masaharu Nagayama, Shin-Ichiro Ei
    CYTOKINE 100 127-127 2017年12月  査読有り
  • Tetsuo Yasugi, Takayuki Yamada, Takashi Nishimura
    SCIENTIFIC REPORTS 7(1) 1619 2017年5月  査読有り
    Trehalose is a non-reducing disaccharide that serves as the main sugar component of haemolymph in insects. Trehalose hydrolysis enzyme, called trehalase, is highly conserved from bacteria to humans. However, our understanding of the physiological role of trehalase remains incomplete. Here, we analyze the phenotypes of several Trehalase (Treh) loss-of-function alleles in a comparative manner in Drosophila. The previously reported mutant phenotype of Treh affecting neuroepithelial stem cell maintenance and differentiation in the optic lobe is caused by second-site alleles in addition to Treh. We further report that the survival rate of Treh null mutants is significantly influenced by dietary conditions. Treh mutant larvae are lethal not only on a low-sugar diet but also under low-protein diet conditions. A reduction in adaptation ability under poor food conditions in Treh mutants is mainly caused by the overaccumulation of trehalose rather than the loss of Treh, because the additional loss of Tps1 mitigates the lethal effect of Treh mutants. These results demonstrate that proper trehalose metabolism plays a critical role in adaptation under various environmental conditions.
  • Sebastian Wissel, Anja Kieser, Tetsuo Yasugi, Peter Duchek, Elisabeth Roitinger, Joseph Gokcezade, Victoria Steinmann, Ulrike Gaul, Karl Mechtler, Klaus Foerstemann, Juergen A. Knoblich, Ralph A. Neumueller
    G3-GENES GENOMES GENETICS 6(8) 2467-2478 2016年8月  査読有り
    Traditional loss-of-function studies in Drosophila suffer from a number of shortcomings, including off-target effects in the case of RNA interference (RNAi) or the stochastic nature of mosaic clonal analysis. Here, we describe minimal in vivo GFP interference (miGFPi) as a versatile strategy to characterize gene function and to conduct highly stringent, cell type-specific loss-of-function experiments in Drosophila. miGFPi combines CRISPR/Cas9-mediated tagging of genes at their endogenous locus with an immunotag and an exogenous 21 nucleotide RNAi effector sequence with the use of a single reagent, highly validated RNAi line targeting this sequence. We demonstrate the utility and time effectiveness of this method by characterizing the function of the Polymerase I (Pol I)-associated transcription factor Tif-1a, and the previously uncharacterized gene MESR4, in the Drosophila female germline stem cell lineage. In addition, we show that miGFPi serves as a powerful technique to functionally characterize individual isoforms of a gene. We exemplify this aspect of miGFPi by studying isoform-specific loss-of-function phenotypes of the longitudinals lacking (lola) gene in neural stem cells. Altogether, the miGFPi strategy constitutes a generalized loss-of-function approach that is amenable to the study of the function of all genes in the genome in a stringent and highly time effective manner.
  • Makoto Sato, Tetsuo Yasugi, Yoshiaki Minami, Takashi Miura, Masaharu Nagayama
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113(35) E5153-E5162 2016年8月  査読有り
    Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt and pepper patterns during various developmental processes. However, how Notch signaling behaves in combination with other signaling systems remains elusive. The wave of differentiation in the Drosophila visual center or "proneural wave" accompanies Notch activity that is propagated without the formation of a salt and pepper pattern, implying that Notch does not form a feedback loop of lateral inhibition during this process. However, mathematical modeling and genetic analysis clearly showed that Notch-mediated lateral inhibition is implemented within the proneural wave. Because partial reduction in EGF signaling causes the formation of the salt and pepper pattern, it is most likely that EGF diffusion cancels salt and pepper pattern formation in silico and in vivo. Moreover, the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a function of Notch signaling that regulates propagation of the wave of differentiation.
  • Takumi Suzuki, Olena Trush, Tetsuo Yasugi, Rie Takayama, Makoto Sato
    JOURNAL OF NEUROSCIENCE 36(24) 6503-6513 2016年6月  査読有り
    During brain development, various types of neuronal populations are produced from different progenitor pools to produce neuronal diversity that is sufficient to establish functional neuronal circuits. However, the molecular mechanisms that specify the identity of each progenitor pool remain obscure. Here, we show that Wnt signaling is essential for the specification of the identity of posterior progenitor pools in the Drosophila visual center. In the medulla, the largest component of the visual center, different types of neurons are produced from two progenitor pools: the outer proliferation center (OPC) and glial precursor cells (GPCs; also known as tips of the OPC). We found that OPC-type neurons are produced from the GPCs at the expense of GPC-type neurons when Wnt signaling is suppressed in the GPCs. In contrast, GPC-type neurons are ectopically induced when Wnt signaling is ectopically activated in the OPC. These results suggest that Wnt signaling is necessary and sufficient for the specification of the progenitor pool identity. We also found that Homothorax (Hth), which is temporally expressed in the OPC, is ectopically induced in the GPCs by suppression of Wnt signaling and that ectopic induction of Hth phenocopies the suppression ofWntsignaling in the GPCs. Thus, Wntsignaling is involved in regionalization of the fly visual center through the specification of the progenitor pool located posterior to the medulla by suppressing Hth expression.
  • Tetsuo Yasugi, Takashi Nishimura
    DEVELOPMENT GROWTH & DIFFERENTIATION 58(1) 73-87 2016年1月  査読有り
    For the construction of complex neural networks, the generation of neurons and glia must be tightly regulated both spatially and temporally. One of the major issues in neural development is the generation of a large variety of neurons and glia over time from a relatively small number of neural stem cells. In Drosophila, neural stem cells, called neuroblasts (NBs), have been used as a useful model system to uncover the molecular and cellular machinery involved in the establishment of neural diversity. NBs divide asymmetrically and produce another self-renewing progenitor cell and a differentiating cell. NBs are subdivided into several types based on their location in the central nervous system. Each type of NB has specific features related to the timing of cell generation, cell cycle progression, temporal patterning for neuronal specification, and termination mechanism. In this review, we focus on the molecular mechanisms that regulate the proliferation of NBs and generate a large variety of neuronal and glia subtypes during development.
  • Tetsuo Yasugi, Anja Fischer, Yanrui Jiang, Heinrich Reichert, Juergen A. Knoblich
    PLOS ONE 9(5) e97034 2014年5月  査読有り
    Neurogenesis is initiated by a set of basic Helix-Loop-Helix (bHLH) transcription factors that specify neural progenitors and allow them to generate neurons in multiple rounds of asymmetric cell division. The Drosophila Daughterless (Da) protein and its mammalian counterparts (E12/E47) act as heterodimerization factors for proneural genes and are therefore critically required for neurogenesis. Here, we demonstrate that Da can also be an inhibitor of the neural progenitor fate whose absence leads to stem cell overproliferation and tumor formation. We explain this paradox by demonstrating that Da induces the differentiation factor Prospero (Pros) whose asymmetric segregation is essential for differentiation in one of the two daughter cells. Da co-operates with the bHLH transcription factor Asense, whereas the other proneural genes are dispensible. After mitosis, Pros terminates Asense expression in one of the two daughter cells. In da mutants, pros is not expressed, leading to the formation of lethal transplantable brain tumors. Our results define a transcriptional feedback loop that regulates the balance between self-renewal and differentiation in Drosophila optic lobe neuroblasts. They indicate that initiation of a neural differentiation program in stem cells is essential to prevent tumorigenesis.
  • Haruhiko Kawamori, Miyako Tai, Makoto Sato, Tetsuo Yasugi, Tetsuya Tabata
    DEVELOPMENT GROWTH & DIFFERENTIATION 53(5) 653-667 2011年6月  査読有り
    A large number of neural and glial cell species differentiate from neuronal precursor cells during nervous system development. Two types of Drosophila optic lobe neurons, lamina and medulla neurons, are derived from the neuroepithelial (NE) cells of the outer optic anlagen. During larval development, epidermal growth factor receptor (EGFR)/Ras signaling sweeps the NE field from the medial edge and drives medulla neuroblast (NB) formation. This signal drives the transient expression of a proneural gene, lethal of scute, and we refer to its signal array as the ``proneural wave,'' as it is the marker of the EGFR /Ras signaling front. In this study, we show that the atypical cadherin Fat and the downstream Hippo pathways regulate the transduction of EGFR /Ras signaling along the NE field and, thus, ensure the progress of NB differentiation. Fat/Hippo pathway mutation also disrupts the pattern formation of the medulla structure, which is associated with the regulation of neurogenesis. A candidate for the Fat ligand, Dachsous is expressed in the posterior optic lobe, and its mutation was observed to cause a similar phenotype as fat mutation, although in a regionally restricted manner. We also show that Dachsous functions as the ligand in this pathway and genetically interacts with Fat in the optic lobe. These findings provide new insights into the function of the Fat/Hippo pathway, which regulates the ordered progression of neurogenesis in the complex nervous system.
  • Tetsuo Yasugi, Atsushi Sugie, Daiki Umetsu, Tetsuya Tabata
    DEVELOPMENT 137(19) 3193-3203 2010年10月  査読有り
    During neurogenesis in the medulla of the Drosophila optic lobe, neuroepithelial cells are programmed to differentiate into neuroblasts at the medial edge of the developing optic lobe. The wave of differentiation progresses synchronously in a row of cells from medial to the lateral regions of the optic lobe, sweeping across the entire neuroepithelial sheet; it is preceded by the transient expression of the proneural gene lethal of scute [l(1)sc] and is thus called the proneural wave. We found that the epidermal growth factor receptor (EGFR) signaling pathway promotes proneural wave progression. EGFR signaling is activated in neuroepithelial cells and induces l(1) sc expression. EGFR activation is regulated by transient expression of Rhomboid (Rho), which is required for the maturation of the EGF ligand Spitz. Rho expression is also regulated by the EGFR signal. The transient and spatially restricted expression of Rho generates sequential activation of EGFR signaling and assures the directional progression of the differentiation wave. This study also provides new insights into the role of Notch signaling. Expression of the Notch ligand Delta is induced by EGFR, and Notch signaling prolongs the proneural state. Notch signaling activity is downregulated by its own feedback mechanism that permits cells at proneural states to subsequently develop into neuroblasts. Thus, coordinated sequential action of the EGFR and Notch signaling pathways causes the proneural wave to progress and induce neuroblast formation in a precisely ordered manner.
  • Atsushi Sugie, Daiki Umetsu, Tetsuo Yasugi, Karl-Friedrich Fischbach, Tetsuya Tabata
    DEVELOPMENT 137(19) 3303-3313 2010年10月  査読有り
    Topographic maps, which maintain the spatial order of neurons in the order of their axonal connections, are found in many parts of the nervous system. Here, we focus on the communication between retinal axons and their postsynaptic partners, lamina neurons, in the first ganglion of the Drosophila visual system, as a model for the formation of topographic maps. Post-mitotic lamina precursor cells differentiate upon receiving Hedgehog signals delivered through newly arriving retinal axons and, before maturing to extend neurites, extend short processes toward retinal axons to create the lamina column. The lamina column provides the cellular basis for establishing stereotypic synapses between retinal axons and lamina neurons. In this study, we identified two cell-adhesion molecules: Hibris, which is expressed in post-mitotic lamina precursor cells; and Roughest, which is expressed on retinal axons. Both proteins belong to the nephrin/NEPH1 family. We provide evidence that recognition between post-mitotic lamina precursor cells and retinal axons is mediated by interactions between Hibris and Roughest. These findings revealed mechanisms by which axons of presynaptic neurons deliver signals to induce the development of postsynaptic partners at the target area. Postsynaptic partners then recognize the presynaptic axons to make ensembles, thus establishing a topographic map along the anterior/posterior axis.
  • Tetsuo Yasugi, Daiki Umetsu, Satoshi Murakami, Makoto Sato, Tetsuya Tabata
    DEVELOPMENT 135(8) 1471-1480 2008年4月  査読有り
    Neural stem cells called neuroblasts (NBs) generate a variety of neuronal and glial cells in the central nervous system of the Drosophila embryo. These NBs, few in number, are selected from a field of neuroepithelial ( NE) cells. In the optic lobe of the third instar larva, all NE cells of the outer optic anlage (OOA) develop into either NBs that generate the medulla neurons or lamina neuron precursors of the adult visual system. The number of lamina and medulla neurons must be precisely regulated because photoreceptor neurons project their axons directly to corresponding lamina or medulla neurons. Here, we show that expression of the proneural protein Lethal of scute [L(1)sc] signals the transition of NE cells to NBs in the OOA. L(1) sc expression is transient, progressing in a synchronized and ordered 'proneural wave' that sweeps toward more lateral NEs. l(1) sc expression is sufficient to induce NBs and is necessary for timely onset of NB differentiation. Thus, proneural wave precedes and induces transition of NE cells to NBs. Unpaired (Upd), the ligand for the JAK/STAT signaling pathway, is expressed in the most lateral NE cells. JAK/STAT signaling negatively regulates proneural wave progression and controls the number of NBs in the optic lobe. Our findings suggest that NBs might be balanced with the number of lamina neurons by JAK/STAT regulation of proneural wave progression, thereby providing the developmental basis for the formation of a precise topographic map in the visual center.
  • M Sato, D Umetsu, S Murakami, T Yasugi, T Tabata
    NATURE NEUROSCIENCE 9(1) 67-75 2006年1月  査読有り
    In Drosophila melanogaster, the axons of retinal photoreceptor cells extend to the first optic ganglion, the lamina, forming a topographic representation. Here we show that DWnt4, a secreted protein of the Wnt family, is the ventral cue for the lamina. In DWnt4 mutants, ventral retinal axons misprojected to the dorsal lamina. DWnt4 was normally expressed in the ventral half of the developing lamina and DWnt4 protein was detected along ventral retinal axons. Dfrizzled2 and dishevelled, respectively, encode a receptor and a signaling molecule required for Wnt signaling. Mutations in both genes caused DWnt4-like defects, and both genes were autonomously required in the retina, suggesting a direct role of DWnt4 in retinal axon guidance. In contrast, iroquois homeobox genes are the dorsal cues for the retina. Dorsal axons accumulated DWnt4 and misprojected to the ventral lamina in iroquois mutants; the phenotype was suppressed in iroquois Dfrizzled2 mutants, suggesting that iroquois may attenuate the competence of Dfrizzled2 to respond to DWnt4.
  • S Yoshida, L Soustelle, A Giangrande, D Umetsu, S Murakami, T Yasugi, T Awasaki, K Ito, M Sato, T Tabata
    DEVELOPMENT 132(20) 4587-4598 2005年10月  査読有り
    The Drosophila visual system consists of the compound eyes and the optic ganglia in the brain. Among the eight photoreceptor (R) neurons, axons from the R1-R6 neurons stop between two layers of glial cells in the lamina, the most superficial ganglion in the optic lobe. Although it has been suggested that the lamina glia serve as intermediate targets of R axons, little is known about the mechanisms by which these cells develop. We show that DPP signaling plays a key role in this process. dpp is expressed at the margin of the lamina target region, where glial precursors reside. The generation of clones mutant for Medea, the DPP signal transducer, or inhibition of DPP signaling in this region resulted in defects in R neuron projection patterns and in the lamina morphology, which was caused by defects in the differentiation of the lamina glial cells. glial cells missing/glial cells deficient (gcm; also known as glide) is expressed shortly after glia precursors start to differentiate and migrate. Its expression depends on DPP; gcm is reduced or absent in dpp mutants or Medea clones, and ectopic activation of DPP signaling induces ectopic expression of gcm and REPO. In addition, R axon projections and lamina glia development were impaired by the expression of a dominant-negative form of gcm, suggesting that gcm indeed controls the differentiation of lamina glial cells. These results suggest that DPP signaling mediates the maturation of the lamina glia required for the correct R axon projection pattern by controlling the expression of gcm.

MISC

 10

講演・口頭発表等

 10

担当経験のある科目(授業)

 2

共同研究・競争的資金等の研究課題

 16