 | ISHINO YugoOriental Medicine Research Institute Lecturer | ||
Last Updated :2024/04/19
Published Papers
- 清水 尚子; 石野 雄吾; 武田 卓; 遠山 正彌; 宮田 信吾産婦人科の実際 金原出版(株) 72 (3) 231 - 235 0558-4728 2023/03＜文献概要＞女性の更年期障害は,卵巣機能低下によるエストロゲン分泌減少などの生物学的要因に加え,社会心理的ストレスなどの環境要因が複雑に関与し,身体的症状や精神的症状を呈する。これらの症状に対し,女性三大漢方薬の1つである加味逍遙散(KSS)が汎用され,特にうつ・不安,イライラなどの精神的症状改善において臨床的評価が高い。本研究は,更年期うつ症状を改善するKSSの作用機序解明を目的とし,更年期うつ病モデルマウスを用いた解析を行った結果,KSSが海馬におけるセロトニン1A(5-HT1A)受容体発現回復およびPKA-CREB-BDNF経路の活性化を介してうつ症状を改善している可能性が示唆された。
- Yugo Ishino; Shoko Shimizu; Masaya Tohyama; Shingo MiyataDevelopmental neurobiology 82 (3) 245 - 260 2022/04Protein arginine methylation has been recognized as one of key posttranslational modifications for refined protein functions, mediated by protein arginine methyltransferases (Prmts). Coactivator-associated arginine methyltransferase (Carm1, also known as Prmt4) participates in various cellular events, such as cell survival, proliferation, and differentiation through its protein arginine methylation activities. Carm1 regulates cell proliferation of a neuronal cell line and is reportedly expressed in the mammalian brain. However, its detailed function in the central nervous system, particularly in glial cells, remains largely unexplored. In this study, Carm1 exhibited relatively high expression in oligodendrocyte (OL) lineage cells present in the corpus callosum of the developing brain, followed by a remarkable downregulation after active myelination. The suppression of Carm1 activity by inhibitors in isolated oligodendrocyte precursor cells (OPCs) reduced the number of Ki67-expressing and BrdU-incorporated proliferating cells. Furthermore, Carm1 inactivation attenuated OL differentiation, as determined by the expression of Plp, a reliable myelin-related marker. It also impaired the extension of OL processes, accompanied by a significant reduction in gene expression related to OL differentiation and myelination, such as Sox10, Cnp, Myrf, and Mbp. In addition, OLs co-cultured with embryonic dorsal root ganglia neurons demonstrated that Carm1 activity is required for the appropriate formation of myelin processes and myelin sheaths around neuronal axons, and the induction of the clustering of Caspr, a node of Ranvier structural molecule. Thus, we propose that Carm1 is an essential molecule for the development of OPCs and OLs during brain development.
- Shingo Miyata; Yugo Ishino; Shoko Shimizu; Masaya TohyamaFrontiers in aging neuroscience 14 934346 - 934346 2022Major depressive disorder (MDD) is a multifactorial disease affected by several environmental factors. Although several potential onset hypotheses have been identified, the molecular mechanisms underlying the pathogenesis of this disorder remain unclear. Several recent studies have suggested that among many environmental factors, inflammation and immune abnormalities in the brain or the peripheral tissues are associated with the onset of MDDs. Furthermore, several stress-related hypotheses have been proposed to explain the onset of MDDs. Thus, inflammation or immune abnormalities can be considered stress responses that occur within the brain or other tissues and are regarded as one of the mechanisms underlying the stress hypothesis of MDDs. Therefore, we introduce several current advances in inflammation studies in the brain that might be related to the pathophysiology of MDD due to stress exposure in this review.
- 更年期障害における精神神経症状を改善する加味逍遙散の作用機序解明清水 尚子; 石野 雄吾; 武田 卓; 遠山 正彌; 宮田 信吾日本自律神経学会総会プログラム・抄録集 日本自律神経学会 74回 108 - 108 2021/10
- Yasufumi Hayano; Yugo Ishino; Jung Ho Hyun; Carlos G Orozco; André Steinecke; Elizabeth Potts; Yasuhiro Oisi; Connon I Thomas; Debbie Guerrero-Given; Eunjoon Kim; Hyung-Bae Kwon; Naomi Kamasawa; Hiroki TaniguchiScience advances 7 (29) 2021/07The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.
- André Steinecke; Nobuhiro Kurabayashi; Yasufumi Hayano; Yugo Ishino; Hiroki TaniguchiCell reports 28 (2) 325 - 331 2019/07 [Refereed]
CRISPR/Cas-based technologies have revolutionized genetic approaches to addressing a wide range of neurobiological questions. The ability of CRISPR/Cas to introduce mutations into target genes allows us to perform in vivo loss-of-function experiments without generating genetically engineered mice. However, the lack of a reliable method to determine genotypes of individual CRISPR/Cas-transfected cells has made it impossible to unambiguously identify the genetic cause of their phenotypes in vivo. Here, we report a strategy for single-cell genotyping in CRISPR/Cas-transfected neurons that were phenotypically characterized in vivo. We show that re-sectioning of cortical slices and subsequent laser microdissection allow us to isolate individual CRISPR/Cas-transfected neurons. Sequencing of PCR products containing a CRISPR/Cas-targeted genomic region in single reference neurons provided genotypes that completely correspond with those deduced from their target protein expression and phenotypes. Thus, our study establishes a powerful strategy to determine the causality between genotypes and phenotypes in CRISPR/Cas-transfected neurons. - Shoko Shimizu; Yugo Ishino; Takashi Takeda; Masaya Tohyama; Shingo MiyataEvidence-based complementary and alternative medicine : eCAM 2019 9475384 - 9475384 1741-427X 2019 [Refereed]
Females are well known to suffer disproportionately more than males from stress-related neuropsychiatric disorders, especially during perimenopausal and postmenopausal periods. In addition to a decline in serum estradiol levels, environmental stress and social stress likely contribute to the development of neuropsychiatric symptoms in perimenopausal and postmenopausal women. Kamishoyosan (KSS) is a traditional Japanese Kampo medicine, composed of a specified mixture of 10 crude compounds derived from plant sources, widely used for various neuropsychiatric symptoms in perimenopausal and postmenopausal women. However, the molecular mechanisms underlying KSS-mediated attenuation of neuropsychological symptoms and stress-response behaviors in perimenopausal and postmenopausal women remain unknown. In the present study, we first established a mouse model for postmenopausal depression-like signs using chronic water-immersion and restraint-stressed ovariectomized (OVX) mice to investigate the underlying molecular mechanism of KSS. We found that continuous administration of KSS to these mice normalized the activation of the hypothalamic-pituitary-adrenal (HPA) axis, ameliorated stress-induced depressive behavior, and prevented a decrease of neurogenesis in the hippocampus. As previous studies have implicated dysfunction of the hippocampal 5-HT1A receptor (5-HT1AR) in depressive disorders, we also evaluated the effect of KSS on 5-HT1AR expression and the protein kinase A- (PKA-) cAMP response element-binding- (CREB-) brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus in this model. The level of 5-HT1AR in the hippocampus decreased in chronic stress-exposed OVX mice, while KSS treatment normalized the stress-induced decrease in 5-HT1AR expression in the hippocampus of chronic stress-exposed OVX mice. Furthermore, we found that KSS treatment upregulated the expression levels of phosphorylated PKA (p-PKA), phosphorylated CREB (p-CREB), and BDNF in the hippocampus in chronic stress-exposed OVX mice. These results suggest that KSS improves neuropsychiatric symptoms through 5-HT1AR and PKA-CREB-BDNF signaling in the hippocampus in postmenopausal women. - Shoko Shimizu; Yugo Ishino; Masaya Tohyama; Shingo MiyataScientific Reports Nature Publishing Group 8 (1) 7644 2045-2322 2018/12 [Refereed]
Oligodendrocytes, the myelin-forming cells in the central nervous system (CNS), undergo morphological differentiation characterized by elaborated branched processes to enwrap neuronal axons. However, the basic molecular mechanisms underlying oligodendrocyte morphogenesis remain unknown. Herein, we describe the essential roles of Nuclear Distribution E Homolog 1 (NDE1), a dynein cofactor, in oligodendrocyte morphological differentiation. In the mouse corpus callosum, Nde1 mRNA expression was detected in oligodendrocyte lineage cells at the postnatal stage. In vitro analysis revealed that downregulation of NDE1 by siRNA impaired the outgrowth and extensive branching of oligodendrocyte processes and led to a decrease in the expression of myelin-related markers, namely, CNPase and MBP. In myelinating co-cultures with dorsal root ganglion (DRG) neurons, NDE1-knockdown oligodendrocyte precursor cells (OPCs) failed to develop into MBP-positive oligodendrocytes with multiple processes contacting DRG axons. Immunoprecipitation studies showed that NDE1 interacts with the dynein intermediate chain (DIC) in oligodendrocytes, and an overexpressed DIC-binding region of NDE1 exerted effects on oligodendrocyte morphogenesis that were similar to those following NDE1 knockdown. Furthermore, NDE1-knockdown-impaired oligodendrocyte process formation was rescued by siRNA-resistant wild-type NDE1 but not by DIC-binding region-deficient NDE1 overexpression. These results suggest that NDE1 plays a crucial role in oligodendrocyte morphological differentiation via interaction with dynein. - Yugo Ishino; Michael J. Yetman; Serena M. Sossi; Andre Steinecke; Yasufumi Hayano; Hiroki TaniguchiJOURNAL OF NEUROSCIENCE SOC NEUROSCIENCE 37 (41) 9901 - 9916 0270-6474 2017/10 [Refereed]
Different cortical regions processing distinct information, such as the hippocampus and the neocortex, share common cellular components and circuit motifs but form unique networks by modifying these cardinal units. Cortical circuits include diverse types of GABAergic interneurons (INs) that shape activity of excitatory principal neurons (PNs). Canonical IN types conserved across distinct cortical regions have been defined by their morphological, electrophysiological, and neurochemical properties. However, it remains largely unknown whether canonical IN types undergo specific modifications in distinct cortical regions and display "regional variants." It is also poorly understood whether such phenotypic variations are shaped by early specification or regional cellular environment. The chandelier cell (ChC) is a highly stereotyped IN type that innervates axon initial segments of PNs and thus serves as a good model with which to address this issue. Here, we show that Cadherin-6 (Cdh6), a homophilic cell adhesion molecule, is a reliable marker of ChCs and Cdh6-CreER mice (both sexes) provide genetic access to hippocampal ChCs (h-ChCs). We demonstrate that, compared with neocortical ChCs (nc-ChCs), h-ChCs cover twice as much area and innervate twice as many PNs. Interestingly, a subclass of h-ChCs exhibits calretinin (CR) expression, which is not found in nc-ChCs. Furthermore, we find that h-ChCs appear to be born earlier than nc-ChCs. Surprisingly, despite the difference in temporal origins, ChCs display host-region-dependent axonal/synaptic organization and CR expression when transplanted heterotopically. These results suggest that local cellular environment plays a critical role in shaping terminal phenotypes of regional IN variants in the hippocampus and the neocortex. - Steinecke A; Hozhabri E; Tapanes S; Ishino Y; Zeng H; Kamasawa N; Taniguchi HeNeuro 4 (3) 2017/05 [Refereed]
- Wen Jiang; Yugo Ishino; Hirokazu Hashimoto; Kazuko Keino-Masu; Masayuki Masu; Kenji Uchirnura; Kenji Kadomatsu; Takeshi Yoshimura; Kazuhiro IkenakaDEVELOPMENTAL NEUROSCIENCE KARGER 39 (5) 361 - 374 0378-5866 2017 [Refereed]
Sulfatases (Su Ifs) are a group of endosulfatases consisting of Sulf1 and Sulf2, which specifically remove sulfate from heparan sulfate proteoglycans. Although several studies have shown that Sulf1 acts as a regulator of sonic hedgehog (Shh) signaling during embryonic ventral spinal cord development, the detailed expression pattern and function of Sulf2 in the spinal cord remains to be determined. In this study, we found that Sulf2 also modulates the cell fate change from motor neurons (MNs) to oligodendrocyte precursor cells (OPCs) by regulating Shh signaling in the mouse ventral spinal cord in coordination with Sulf1. In the mouse, Sulf nnRNAs colocalize with Shh mRNA and gradually expand dorsally from embryonic day (E) 10.5 to E12.5, following strong Patchedl signals (a target gene of Shh signaling). This coordinated expression pattern led us to hypothesize that in the mouse, strong Shh signaling is induced when Shh is released by Sulf1/2, and this strong Shh signaling subsequently induces the dorsal expansion of Shh and Sulf1/2 expression. Consistent with this hypothesis, in the ventral spinal cord of Sulf1 knockout (KO) or Sulf2 KO mice, the expression patterns of Shh and Patchedl differed from that in wild-type mice. Moreover, the position of the pMN and p3 domains were shifted ventrally, MN generation was prolonged, and OPC generation was delayed at E12.5 in both Sulf1 KO and Sulf2 KO mice. These results demonstrated that in addition to Sulfl, Sulf2 also plays an important and overlapping role in the MN-to-OPC fate change by regulating Shh signaling in the ventral spinal cord. However, neither Sulfl nor Sulf2 could compensate for the loss of the other in the developing mouse spinal cord. In vitro studies showed no evidence of an interaction between Sulf1 and Sulf2 that could increase sulfatase activity. Furthermore, Sulf1/2 double heterozygote and Sulf1/2 double KO mice exhibited phenotypes similar to the Sulf1 KO and Sulf2 KO mice. These results indicate that there is a threshold for sulfatase activity (which is likely reflected in the dose of Shh) required to induce the MN-to-OPC fate change, and Shh signaling requires the coordinated activity of Sulf1 and Sulf2 in order to reach that threshold in the mouse ventral spinal cord. (C) 2017 S. Karger AG, Basel - Masae Naruse; Yugo Ishino; Akhilesh Kumar; Katsuhiko Ono; Hirohide Takebayashi; Masahiro Yamaguchi; Yasuki Ishizaki; Kazuhiro Ikenaka; Seiji HitoshiCEREBRAL CORTEX OXFORD UNIV PRESS INC 26 (6) 2800 - 2810 1047-3211 2016/06 [Refereed]
Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligodendrocytes (OLs), and form myelin in the postnatal brain. Recently, it has been proposed that early-born OPCs derived from the ventral forebrain are eradicated postnatally and that late-born OLs predominate in the cortex of the adult mouse brain. However, intrinsic and extrinsic factors that specify the ability of self-renewing multipotent neural stem cells in the embryonic brain to generate cortical OL-lineage cells remain largely unknown. Using an inducible Cre/loxP system to permanently label Nestin- and Olig2-lineage cells, we identified that cortical OL-lineage cells start differentiating from neural stem cells within a restricted temporal window just prior to E16.5 through P10. We then showed, by means of electroporation of a Cre expression plasmid into the VZ/SVZ of E15.5 reporter mouse brains, that neural precursor cells in the dorsal VZ/SVZ are inhibited by Wnt signaling from contributing to cortical OLs in the adult brain. In contrast, neural precursor cells present in the dorsoventral boundary VZ/SVZ produce a significant amount of OLs in the adult cortex. Our results suggest that neural stem cells at this boundary are uniquely specialized to produce myelin-forming OLs in the cortex. - Hirokazu Hashimoto; Yugo Ishino; Wen Jiang; Takeshi Yoshimura; Yoshiko Takeda-Uchimura; Kenji Uchimura; Kenji Kadomatsu; Kazuhiro IkenakaNEUROCHEMICAL RESEARCH SPRINGER/PLENUM PUBLISHERS 41 (1-2) 450 - 462 0364-3190 2016/02 [Refereed]
Keratan sulfate (KS) is a sulfated glycosaminoglycan and has been shown to bind to sonic hedgehog (Shh), which act as a morphogen to regulate the embryonic spinal cord development. We found highly sulfated KS was present in the floor plate (including lateral floor plate) and the notochord . This expression colocalized with Shh expression. To understand the roles of KS, we analyzed the embryonic spinal cord of GlcNAc6ST-1, KS chain synthesizing enzyme, knock-out (KO) mice. At E12.5, the pMN domain, whose formation is controlled by Shh signaling, became shifted ventrally in GlcNAc6ST-1 KO mice. In addition, the expression patterns of Patched1 and Gli1, two Shh signaling reporter genes, differed between wild type (WT) and GlcNAc6ST-1 KO mice at E12.5. Next, we focused on cell types generated from the pMN domain; namely, motor neurons and subsequently oligodendrocytes. The number of PDGFR alpha(+) [a marker for oligodendrocyte precursor cells (OPCs)] cells was low in the E12.5 mutant spinal cord, while motor neuron production was increased. Thus the switch from motor neuron generation to OPC generation was delayed in the pMN domain. Furthermore, we investigated the cause for this delayed switch in the pMN domain. The number of Olig2, Nkx2.2 double-positive cells was less in GlcNAc6ST-1 KO mice than in WT mice. In contrast, the number of Olig2, Neurogenin2 (Ngn2) double-positive cells related to the motor neuron specification was significantly greater in the KO mice. These results indicate that KS is important for the late phase Shh signaling and contributes to motor neuron to OPC generation switch. - Shoko Shimizu; Takashi Tanaka; Masaya Tohyama; Shingo MiyataBRAIN RESEARCH BULLETIN PERGAMON-ELSEVIER SCIENCE LTD 114 49 - 55 0361-9230 2015/05 [Refereed]
Stressful events are known to down-regulate expression levels of glucocorticoid receptors (GRs) in the brain. Recently, we reported that stressed mice with elevated plasma levels of corticosterone exhibit morphological changes in the oligodendrocytes of nerve fiber bundles, such as those in the corpus callosum. However, little is known about the molecular mechanism of GR expression regulation in oligodendrocytes after stress exposure. A previous report has suggested that GR protein levels might be regulated by microRNA (miR)-18 and/or -124a in the brain. In this study, we aimed to elucidate the GR regulation mechanism in oligodendrocytes and evaluate the effects of yokukansan (YKS), a Kampo medicine, on GR protein regulation. Acute exposure to stress increased plasma corticosterone levels, decreased GR protein expression, and increased miR-124a expression in the corpus callosum of adult male mice, though the GR mRNA and miR-18 expression levels were not significant changes. YKS normalized the stress-induced changes in the plasma corticosterone, GR protein, and miR124a expression levels. An oligodendrocyte primary culture study also showed that YKS down-regulated miR-124a, but not miR-18, expression levels in dexamethasone-treated cells. These results suggest that the down-regulation of miR124a expression might be involved in the normalization of stress-induced decreases in GR protein in oligodendrocytes by YKS. This effect may imply the molecular mechanisms underlying the ameliorative effects of YKS on psychological symptoms and stress-related behaviors. (C) 2015 Elsevier Inc. All rights reserved. - Yugo Ishino; Yoshitaka Hayashi; Masae Naruse; Koichi Tomita; Makoto Sanbo; Takahiro Fuchigami; Ryoji Fujiki; Kenzo Hirose; Yayoi Toyooka; Toshihiko Fujimori; Kazuhiro Ikenaka; Seiji HitoshiJOURNAL OF NEUROSCIENCE SOC NEUROSCIENCE 34 (8) 3067 - 3078 0270-6474 2014/02 [Refereed]
Cell cycle regulation is crucial for the maintenance of stem cell populations in adult mammalian tissues. During development, the cell cycle length in neural stem cells increases, which could be associated with their capabilities for self-renewal. However, the molecular mechanisms that regulate differentiation and cell cycle progression in embryonic neural stem cells remain largely unknown. Here, we investigated the function of Bre1a, a histone H2B ubiquitylation factor, which is expressed in most but not all of neural precursor cells (NPCs) in the developing mouse brain. We found that the knockdown of Bre1a in NPCs lengthened their cell cycle through the upregulation of p57(kip2) and the downregulation of Cdk2. In addition, the knockdown of Bre1a increased the expression of Hes5, an effector gene of Notch signaling, through the action of Fezf1 and Fezf2 genes and suppressed the differentiation of NPCs. Our data suggest that Bre1a could be a bifunctional gene that regulates both the differentiation status and cell cycle length of NPCs. We propose a novel model that the Bre1a-negative cells in the ventricular zone of early embryonic brains remain undifferentiated and are selected as self-renewing neural stem cells, which increase their cell cycle time during development. - Akhilesh Kumar; Tomohiro Torii; Yugo Ishino; Daisuke Muraoka; Takeshi Yoshimura; Akira Togayachi; Hisashi Narimatsu; Kazuhiro Ikenaka; Seiji HitoshiThe Journal of biological chemistry 288 (40) 28859 - 68 0021-9258 2013/10 [Refereed]
Lewis X (Le(X), Galβ1-4(Fucα1-3)GlcNAc) is a carbohydrate epitope that is present at the nonreducing terminus of sugar chains of glycoproteins and glycolipids, and is abundantly expressed in several stem cell populations. Le(X) antigen can be used in conjunction with fluorescence-activated cell sorting to isolate neurosphere-forming neural stem cells (NSCs) from embryonic mouse brains. However, its function in the maintenance and differentiation of stem cells remains largely unknown. In this study, we examined mice deficient for fucosyltransferase 9 (Fut9), which is thought to synthesize most, if not all, of the Le(X) moieties in the brain. We found that the number of NSCs was increased in the brain of Fut9(-/-) embryos, suggesting that Fut9-synthesized Le(X) is dispensable for the maintenance of NSCs. Another α1,3-fucosyltransferase gene, fucosyltransferase 10 (Fut10), is expressed in the ventricular zone of the embryonic brain. Overexpression of Fut10 enhanced the self-renewal of NSCs. Conversely, suppression of Fut10 expression induced the differentiation of NSCs and embryonic stem cells. In addition, knockdown of Fut10 expression in the cortical ventricular zone of the embryonic brain by in utero electroporation of Fut10-miRNAs impaired the radial migration of neural precursor cells. Our data suggest that Fut10 is involved in a unique α1,3-fucosyltransferase activity with stringent substrate specificity, and that this activity is required to maintain stem cells in an undifferentiated state. - Hanae Nodono; Yugo Ishino; Motonori Hoshi; Midori MatsumotoMOLECULAR REPRODUCTION AND DEVELOPMENT WILEY-BLACKWELL 79 (11) 757 - 766 1040-452X 2012/11 [Refereed]
Planarian species may harbor as many as three populations with different reproductive strategies. Animals from innate asexual (AS) and innate sexual (InS) populations reproduce only by fission and cross-fertilization, respectively, whereas the third population switches seasonally between the two reproductive modes. AS worms can be experimentally sexualized by feeding them with minced InS worms; we termed the resulting animals acquired sexual (AqS) worms. Both AqS and InS worms exhibit sexualizing activity when used as feed, suggesting that they maintain their sexual state via endogenous sexualizing substances, although the mechanisms underlying determination of reproductive strategy and sexual switching in these metazoans remain enigmatic. Therefore, we compared the endogenous sexualizing activity of InS worms and AqS worms. First, we amputated mature worms and assessed if they could re-enter a sexual state. Regenerants of InS worms, but not AqS worms, were only sexual, indicating that sexual state regulation comprises two steps: (1) autonomous initiation of sexualizing substance production and (2) maintenance of the sexual state by continuous production of sexualizing substances. Next, InS neoblasts were characterized by transplantation, finding that they successfully engrafted, proliferated, and replaced all recipient cells. Under such conditions, the AS recipients of InS worm neoblasts, but not those of AqS worms, became sexual. These results clearly show that there is a neoblast-autonomous determination of reproductive strategy in planarians. Mol. Reprod. Dev. 79: 757766, 2012. (C) 2012 Wiley Periodicals, Inc. - Seiji Hitoshi; Yugo Ishino; Akhilesh Kumar; Salma Jasmine; Kenji F. Tanaka; Takeshi Kondo; Shigeaki Kato; Toshihiko Hosoya; Yoshiki Hotta; Kazuhiro IkenakaNATURE NEUROSCIENCE NATURE PUBLISHING GROUP 14 (8) 957 - U35 1097-6256 2011/08 [Refereed]
Signaling mediated by Notch receptors is crucial for the development of many organs and the maintenance of various stem cell populations. The activation of Notch signaling is first detectable by the expression of an effector gene, Hes5, in the neuroepithelium of mouse embryos at embryonic day (E) 8.0-8.5, and this activation is indispensable for the generation of neural stem cells. However, the molecular mechanism by which Hes5 expression is initiated in stem-producing cells remains unknown. We found that mammalian Gcm1 and Gcm2 (glial cells missing 1 and 2) are involved in the epigenetic regulation of Hes5 transcription by DNA demethylation independently of DNA replication. Loss of both Gcm genes and subsequent lack of Hes5 upregulation in the neuroepithelium of E7.5-8.5 Gcm1(-/-); Gcm2(-/-) mice resulted in the impaired induction of neural stem cells. Our data suggest that Hes5 expression is serially activated first by Gcms and later by the canonical Notch pathway. - Kazuya Kobayashi; Toshiyuki Hashiguchi; Taiichiro Ichikawa; Yugo Ishino; Motonori Hoshi; Midori MatsumotoDEVELOPMENT GROWTH & DIFFERENTIATION BLACKWELL PUBLISHING 50 (8) 689 - 696 0012-1592 2008/10 [Refereed]
Planarians are well known for their remarkable regenerative capacity. This capacity to regenerate is thought to be due to the presence of totipotent somatic stem cells known as 'neoblasts', which have particular morphological characteristics. The totipotency of neoblasts was supported by Baguna's experiment, which involved the introduction of donor cells into irradiated hosts. However, since Baguna's experiment did not include the use of a phenotypic marker, the donor cells could not be traced. In the current study, a genetic mutant planarian, menashi, an eye-defective mutant that lacks the pigmented area in the eyes, was established. This planarian is excellent for tracing the fate of cells after their introduction into irradiated hosts. To investigate the differentiation potency more directly, a neoblast-rich fraction obtained from normal worms was transplanted into an X-ray-irradiated menashi strain. Planarians that survive X-ray irradiation were developed, and we observed the pigment of the area in the eyes of the regenerating planarians. This result suggests that the neoblast-rich fraction contains cells that can proliferate and differentiate. These cells can replace the cells and structures lost by X-ray irradiation and ablation, and they can also differentiate into eye pigment cells.
MISC
- Masae Naruse; Yugo Ishino; Akhilesh Kumar; Katsuhiko Ono; Hirohide Takebayashi; Masahiro Yamaguchi; Kazuhiro Ikenaka; Seiji Hitoshi NEUROSCIENCE RESEARCH 71- E65 -E65 2011
- Yugo Ishino; Akhilesh Kumar; Masae Naruse; Seiji Hitoshi; Kazuhiro Ikenaka NEUROSCIENCE RESEARCH 68- E133 -E133 2010
- マウスglial cells missing遺伝子は初期胚におけるHes5発現を誘導する(Mammalian glial cells missing genes induce Hes5 expression and definitive neural stem cells in early embryos)等 誠司; クマール・アキレッシュ; 石野 雄吾; 田中 謙二; 細谷 俊彦; 堀田 凱樹; 池中 一裕 神経化学 48- (2-3) 204 -204 2009/06
- 石野 雄吾; 等 誠司 メディカルバイオ 6- (2) 36 -41 2009/03
- Seiji Hitoshi; Kumar Akhilesh; Yugo Ishino; Kenji F. Tanaka; Toshihiko Hosoya; Yoshiki Hotta; Kazuhiro Ikenaka NEUROSCIENCE RESEARCH 65- S55 -S55 2009
Awards & Honors
- 2022/07 近畿大学医学会 近畿大学医学会賞
Coactivator-associated arginine methyltransferase 1 controls oligodendrocyte differentiation in the corpus callosum during early brain development
Research Grants & Projects
- Japan Society for the Promotion of Science：Grants-in-Aid for Scientific ResearchDate (from‐to) : 2023/04 -2026/03Author : 宮田 信吾; 遠山 正彌; 清水 尚子; 石野 雄吾
- ストレス性精神症状改善に向けた抑肝散によるmicroRNA制御機構の解明文部科学省：科学研究費助成事業(基盤研究C)Date (from‐to) : 2019/04 -2021/03Author : 遠山正彌
- 腸内細菌叢・脳軸からみた月経前症候群への新治療戦略文部科学省：科学研究費助成事業(基盤研究C)Date (from‐to) : 2019/04 -2021/03Author : 武田卓
- 文部科学省：科学研究費助成事業(若手研究)Date (from‐to) : 2019/04 -2021/03Author : 石野雄吾
- Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)Date (from‐to) : 2014/04 -2017/03Author : IKENAKA Kazuhiro; YOSHIMURA Takeshi; ISHINO Yugo; HASHIMOTO Hirokazu; JIANG WenSulf1/2 are endosulfatases that remove sulfate from heparan sulfate. We found that Sulf2 modulates the cell fate change from motor neurons to oligodendrocyte precursor cells (MN-to-OPC) by regulating Shh signaling in the mouse ventral spinal cord in coordination with Sulf1. Sulf mRNAs colocalized with Shh mRNA and gradually expanded dorsally from E10.5 to E12.5, following strong Patched1 signals (inducec by Shh). In the spinal cord of Sulf1 or 2 knockout (KO) mice, expression patterns of Shh and Patched1 differed from that of wild type mice. Moreover, the position of the ventral domains was shifted ventrally, MN generation prolonged, and OPC generation delayed at E12.5 in KO mice. These results demonstrated that in addition to Sulf1, Sulf2 also plays an important role in the MN-to-OPC fate change by regulating Shh signaling. Strong Shh signaling is induced when Shh is released by Sulf1/2, and this strong Shh input subsequently induces the dorsal expansion of Shh and Sulf1/2 expression.