sfk/published_papers/31624361 Izumi Ohigashi Melina Frantzeskakis Alison Jacques Sayumi Fujimori Aya Ushio Fusano Yamashita Naozumi Ishimaru Da Yin Margaret Cam Michael C Kelly Parirokh Awasthi Kensuke Takada Yousuke Takahama The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection. The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells; however, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here, we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla; independent of additional antigen-presenting cells, including medullary thymic epithelial cells and dendritic cells; and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus. The Journal of experimental medicine 218 4 null null 20210405 10.1084/jem.20201904 33555295 sfk/published_papers/13052203 Izumi Ohigashi Yu Tanaka Kenta Kondo Sayumi Fujimori Hiroyuki Kondo Amy C Palin Victoria Hoffmann Mina Kozai Yosuke Matsushita Shinsuke Uda Ryo Motosugi Jun Hamazaki Hiroyuki Kubota Shigeo Murata Keiji Tanaka Toyomasa Katagiri Hidetaka Kosako Yousuke Takahama Trans-omics Impact of Thymoproteasome in Cortical Thymic Epithelial Cells. The thymic function to produce self-protective and self-tolerant T cells is chiefly mediated by cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs). Recent studies including single-cell transcriptomic analyses have highlighted a rich diversity in functional mTEC subpopulations. Because of their limited cellularity, however, the biochemical characterization of TECs, including the proteomic profiling of cTECs and mTECs, has remained unestablished. Utilizing genetically modified mice that carry enlarged but functional thymuses, here we show a combination of proteomic and transcriptomic profiles for cTECs and mTECs, which identified signature molecules that characterize a developmental and functional contrast between cTECs and mTECs. Our results reveal a highly specific impact of the thymoproteasome on proteasome subunit composition in cTECs and provide an integrated trans-omics platform for further exploration of thymus biology. Cell reports 29 9 2901 2916 20191126 10.1016/j.celrep.2019.10.079 31775054 sfk/published_papers/720107 Umme Shahina Khanom Izumi Ohigashi Sayumi Fujimori Kenta Kondo Kensuke Takada Yousuke Takahama TCR Affinity for In Vivo Peptide-Induced Thymic Positive Selection Fine-Tunes TCR Responsiveness of Peripheral CD8+ T Cells. The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4+CD8+ thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8+ T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8+ T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells. Journal of immunology (Baltimore, Md. : 1950) 0022-1767 203 4 881 887 20190815 10.4049/jimmunol.1900097 31235550 sfk/published_papers/13686085 Masayuki Furuya Junichi Kikuta Sayumi Fujimori Shigeto Seno Hiroki Maeda Mai Shirazaki Maki Uenaka Hiroki Mizuno Yoriko Iwamoto Akito Morimoto Kunihiko Hashimoto Takeshi Ito Yukihiro Isogai Masafumi Kashii Takashi Kaito Shinsuke Ohba Ung-Il Chung Alexander C Lichtler Kazuya Kikuchi Hideo Matsuda Hideki Yoshikawa Masaru Ishii Direct cell-cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo. Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial-temporal relationship and mode of interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell-cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell-cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell-cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo. Nature communications 9 1 300 300 20180119 10.1038/s41467-017-02541-w 29352112 sfk/published_papers/13686009 Teerawan Rattanapak James C. Birchall Katherine Young Atsuko Kubo Sayumi Fujimori Masaru Ishii Sarah Hook Dynamic Visualization of Dendritic Cell-Antigen Interactions in the Skin Following Transcutaneous Immunization PLOS ONE 1932-6203 9 2 null null 20140200 10.1371/journal.pone.0089503 24586830 2-s2.0-84896065891 sfk/published_papers/13686014 Otso Haara Sayumi Fujimori Ruth Schmidt-Ullrich Christine Hartmann Irma Thesleff Marja L. Mikkola Ectodysplasin and Wnt pathways are required for salivary gland branching morphogenesis DEVELOPMENT 0950-1991 138 13 2681 2691 20110700 10.1242/dev.057711 21652647 2-s2.0-79958122194 sfk/published_papers/13686015 Sayumi Fujimori Hermann Novak Martina Weissenboeck Martina Weissenböck Maria Jussila Alexandre Goncalves Alexandre Gonçalves Rolf Zeller Jenna Galloway Irma Thesleff Christine Hartmann Wnt/beta-catenin signaling in the dental mesenchyme regulates incisor development by regulating Bmp4 Wnt/β-catenin signaling in the dental mesenchyme regulates incisor development by regulating Bmp4 DEVELOPMENTAL BIOLOGY Developmental Biology 0012-1606 348 1 97 106 20101200 10.1016/j.ydbio.2010.09.009 2-s2.0-78149410157 sfk/published_papers/13686089 Masaki Fukui Noritaka Nakamichi Masanori Yoneyama Shusuke Ozawa Sayumi Fujimori Yoshifumi Takahata Nobuhiro Nakamura Hideo Taniura Yukio Yoneda Modulation of cellular proliferation and differentiation through GABA(B) receptors expressed by undifferentiated neural progenitor cells isolated from fetal mouse brain JOURNAL OF CELLULAR PHYSIOLOGY 0021-9541 216 2 507 519 20080800 10.1002/jcp.21422 18302163 sfk/published_papers/38175144 Eiichi Hinoi Takeshi Takarada Sayumi Fujimori Liyang Wang Mika Iemata Kyosuke Uno Yukio Yoneda Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis BONE 8756-3282 40 2 337 344 20070200 10.1016/j.bone.2006.08.016 sfk/published_papers/13686025 Sayumi Fujimori Eiichi Hinoi Takeshi Takarada Mika Iemata Yoshifumi Takahata Yukio Yoneda Possible expression of a particular gamma-aminobutyric acid transporter isoform responsive to upregulation by hyperosmolarity in rat calvarial osteoblasts EUROPEAN JOURNAL OF PHARMACOLOGY 0014-2999 550 1-3 24 32 20061100 10.1016/j.ejphar.2006.08.088 17022965 2-s2.0-33750023446 sfk/published_papers/38175145 Eiichi Hinoi Takeshi Takarada Yuriko Tsuchihashi Sayumi Fujimori Nobuaki Moriguchi Liyang Wang Kyosuke Uno Yukio Yoneda A molecular mechanism of pyruvate protection against cytotoxicity of reactive oxygen species in osteoblasts MOLECULAR PHARMACOLOGY 0026-895X 70 3 925 935 20060900 10.1124/mol.106.024398 sfk/published_papers/26541174 Hinoi E Fujimori S Wang L Hojo H Uno K Yoneda Y Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. The Journal of biological chemistry 0021-9258 281 26 18015 18024 20060600 10.1074/jbc.M600603200 16613847 sfk/published_papers/13686034 Sayumi Fujimori Masato Osawa Mika Iemata Eiichi Hinoi Yukio Yoneda Increased GABA transport activity in rat calvarial osteoblasts cultured under hyperglycemic conditions Pharmaceutical Society of Japan Biological and Pharmaceutical Bulletin 1347-5215 29 2 297 301 20060000 10.1248/bpb.29.297 16462035 2-s2.0-32044445778 sfk/published_papers/13686036 Eiichi Hinoi Sayumi Fujimori Yukio Yoneda Modulation of cellular differentiation by N-methyl-D-aspartate receptors in osteoblasts. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 1532 1534 20030101 12824297 2-s2.0-0041703024 sfk/published_papers/34273800 Eiichi Hinoi Sayumi Fujimori Masanori Yoneyama Yukio Yoneda Blockade by N-methyl-D-aspartate of elevation of activator protein-1 binding after stress in rat adrenal gland Wiley Journal of Neuroscience Research 1097-4547 70 2 161 171 20021015 10.1002/jnr.10310 sfk/published_papers/13686039 Sayumi Fujimori Eiichi Hinoi Yukio Yoneda Functional GABAB receptors expressed in cultured calvarial osteoblasts Biochemical and Biophysical Research Communications 0006-291X 293 5 1445 1452 20020000 10.1016/S0006-291X(02)00405-9 12054677 2-s2.0-0036076754 sfk/misc/10599272 Shinji Takada Sayumi Fujimori Takuma Shinozuka Ritsuko Takada Yusuke Mii Differences in the secretion and transport of Wnt proteins JOURNAL OF BIOCHEMISTRY 1756-2651 161 1 1 7 20170100 10.1093/jb/mvw071 28053142 sfk/misc/14784638 Masaru Ishii Sayumi Fujimori Takeshi Kaneko Junichi Kikuta Dynamic live imaging of bone: Opening a new era with 'bone histodynametry' Journal of Bone and Mineral Metabolism 0914-8779 31 5 507 511 20130000 10.1007/s00774-013-0437-x 23546817 2-s2.0-84885409987 sfk/misc/10599725 Sayumi Fujimori Daniela Kostanova-Poliakova Christine Hartmann Role of Growth Factors in Bone Development and Differentiation Cold Spring Harbor Laboratory Press The Skeletal System 53 219 261 20090000 sfk/misc/10599261 Sayumi Fujimori Yukio Yoneda Neuropsychiatric disorders and GABA Japanese Journal of Neuropsychopharmacology 1340-2544 24 5 265 271 20041000 15658502 2-s2.0-11144260088