DOCSLIB.ORG

IL-6 B and Κ Foxj1-Mediated Antagonism of NF- Restraint of B

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IL-6 B and Κ Foxj1-Mediated Antagonism of NF- Restraint of B Restraint of B Cell Activation by Foxj1-Mediated Antagonism of NF- κB and IL-6 This information is current as Ling Lin, Steven L. Brody and Stanford L. Peng of September 27, 2021. J Immunol 2005; 175:951-958; ; doi: 10.4049/jimmunol.175.2.951 http://www.jimmunol.org/content/175/2/951 Downloaded from References This article cites 32 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/175/2/951.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Restraint of B Cell Activation by Foxj1-Mediated Antagonism of NF-␬B and IL-61 Ling Lin,* Steven L. Brody,† and Stanford L. Peng2*‡ The forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity, in part by antagonizing NF-␬B activation in T cells. We demonstrate here that Foxj1 also inhibits humoral immune responses intrinsically in B cells; Foxj1 deficiency in B cells results in spontaneous and accentuated germinal center formation, associated with the development of pathogenic autoantibodies and accentuated responses to immunizations—all reflecting excessive activity of NF-␬B and its target gene IL-6, and correlating with a requirement for Foxj1 to regulate the inhibitory NF-␬B component I␬B␤. Thus, Foxj1 restrains B cell activation and the maturation of humoral responses, demonstrating a critical role for at least this forkhead transcription factor in the regulation of B lymphocyte homeostasis. The Journal of Immunology, 2005, 175: 951–958. Downloaded from ystemic autoimmune syndromes like lupus reflect patho- date the B cell-intrinsic function(s) of Foxj1, particularly its rela- genic, hyperactive T and B cell responses that culminate in tionship to Ag-specific Ab responses. We find that Foxj1 modu- S the production of pathogenic autoantibodies, such as anti- lates germinal center B cell formation in vivo via its ability to dsDNA (1). Recent studies suggest that deficient functions in fork- inhibit the NF-␬B-regulated cytokine IL-6 (7, 8). Foxj1 appears to head transcription factors, such as Foxj1 and Foxo3a, predispose to prevent inappropriate B cell responses at least in part by antago- such diseases, because their activities are significantly diminished nizing NF-␬B target genes like IL-6, which would otherwise prop- http://www.jimmunol.org/ in lupus lymphocytes and their deficiency results in spontaneous, agate pathogenic autoimmune responses through dysregulated B multisystem autoimmune syndromes characterized by autoreac- cell hyperactivation. tive, hyperactivated T cells (2, 3). Presumably, such hyperacti- vated T cells can promote pathogenic autoantibody production by Materials and Methods overexpressing costimulatory molecules and/or effector cytokines, Mice resulting in excessive autoreactive B cell activation. However, a 129, BALB/c, C57BL/6, C57BL/6-IgH , C57BL/6-CD45.1, BXSB, F1 both Foxj1 and Foxo3a are also expressed in B cells (2), and a (NZW ϫ NZB), MRL/ϩ, MRL/lpr, and athymic C57BL/6-nu/nu mice potential immunoregulatory role for the forkhead genes in B cells (The Jackson Laboratory), Rag-2Ϫ/Ϫ (Taconic Farms), and C57BL/6 Foxj1 Ϫ/Ϫ mice (9) were maintained under specific pathogen-free conditions at remains as yet undefined. by guest on September 27, 2021 Pathogenic autoantibody responses require somatic hypermuta- the Washington University School of Medicine. As judged by microsatel- lite markers, mice mutant for Foxj1, which is located on chromosome 11 tion and class switching of natural autoantibodies, such as in the at 78.0 cM, were homozygotic for C57BL/6 loci, including marker context of T-dependent germinal centers, to develop high-affinity, D11Mit333 (66.0 cM; 11qter is ϳ80.0 cM), indicating a Ͻ15 cM residual pathogenic activities, e.g., the production of anti-dsDNA from 129 contribution on chromosome 11. Foxj1 ϩ/ϩ and Ϫ/Ϫ fetal liver chi- 3 germline-encoded anti-ssDNA specificities (1, 4). Most circulating meras (FLCs) were generated in irradiated Rag-2-deficient hosts as pre- viously described (2). For B cell-only chimeras (BOC), fetal livers from natural autoantibodies are produced by natural Ab-secreting B Foxj1 ϩ/ϩ vs Ϫ/Ϫ (CD45.2ϩIgHb) embryos were adoptively transferred cells, such as B1 cells, or by plasma cells that have not undergone into irradiated C57BL/6-nu/nu hosts, and reconstitution of the peripheral B either affinity maturation or class switch recombination (5, 6). As cell lineage was allowed for 8–12 wk. Then, splenic B cell populations a result, the entry of an autoreactive B cell, when activated, into a were purified by negative selection against CD43 (Miltenyi Biotec), and adoptively transferred into C57BL/6-IgHa (for serological studies) or germinal center reaction, therefore, may contribute to and/or un- ϩ C56BL/6-CD45.1 (for flow cytometric studies) animals (one spleen derlie systemic autoimmune diseases like lupus (4, 6). equivalent, ϳ30–40 million B cells, per recipient), and animals were stud- To investigate the role of Foxj1 in B cells, we initiated a series ied 1–2 wk thereafter, as indicated in the text. All experiments were per- of experiments, including adoptive transfers, to isolate and eluci- formed in compliance with the relevant laws and institutional guidelines, as overseen by the Animal Studies Committee of the Washington University School of Medicine. * Division of Rheumatology and †Division of Pulmonary and Critical Care Medicine, In vivo studies Department of Internal Medicine and ‡Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Immunizations with 4-hydroxy-3-nitrophenylacetyl (NP)-chicken ␥ glob- ulin and NP-Ficoll were performed with 50 ␮g of Ag in PBS (without Received for publication March 10, 2005. Accepted for publication May 13, 2005. adjuvant) administered i.p. as previously described (4). Where indicated, The costs of publication of this article were defrayed in part by the payment of page animals were treated with neutralizing anti-IL-6 (MP5-20F3; BD Pharm- charges. This article must therefore be hereby marked advertisement in accordance ingen) or control rat IgG Ab, 5 mg i.p. three times per week (10); or with with 18 U.S.C. Section 1734 solely to indicate this fact. RELA/p65 antisense (5Ј-GAAACAGATCGTCCATGGT) or mismatch 1 This work was supported in part by the Rheumatic Diseases, Siteman Cancer, Di- (5Ј-GGAACAGTTCGTCTATGGC) oligonucleotides, 800 ␮g i.v. daily abetes Research and Training, and the Digestive Diseases Research Core (DK52574) (11). ELISA-based serological assessments, including determination of anti- Centers of the Washington University School of Medicine, as well as grants from the ssDNA using sheared salmon sperm DNA, anti-dsDNA using Crithidia National Institutes of Health (AI057471 and AI061478 to S.L.P.), Arthritis Founda- luciliae immunofluorescence, IgK rheumatoid factor (RF) activity using tion, and the Lupus Research Institute. S.L.P. is supported in part by an Arthritis Investigator Award from the Arthritis Foundation. 2 Address correspondence and reprint requests to Dr. Stanford L. Peng, Washington 3 Abbreviations used in this paper: FLC, fetal liver chimera; BOC, B cell-only chi- University School of Medicine, Campus Box 8045, Clinical Sciences Research Building mera; NP, 4-hydroxy-3-nitrophenylacetyl; PNA, peanut agglutinin; RF, rheumatoid 6617, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: [email protected] factor. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 952 ROLE OF Foxj1 IN B CELLS Table I. B cell characteristics of Foxj1 BOCsa B Cells (B220ϩ) NP-Binding GC-Like (PNAϩB220ϩ) Splenocytes Percentage of Chimeric Percentage of Chimeric Percentage of Chimeric Donor n (ϫ10Ϫ6) splenocytes (%) splenocytes (%) B cells (%) WT 5 67.0 Ϯ 2.5 62.2 Ϯ 1.5 2.2 Ϯ 0.16 2.2 Ϯ 0.32 2.6 Ϯ 0.38 3.9 Ϯ 1.1 2.7 Ϯ 0.3 Ϯ 0.13 5.6 Ϯ 0.32b 20.6 Ϯ 2.4b 52 Ϯ 4.3b 2.8 ءKO 5 68.8 Ϯ 3.8 64.6 Ϯ 4.2 9.9 Ϯ 0.76 a BOCs were generated first by chimerization of nu/nu animals by Foxj1 ϩ/ϩ or Ϫ/Ϫ fetal livers (CD45.2), the B cells of which were then adoptively transferred into wild-type C57BL/6-CD45.1 animals. Shown are flow cytometric data (means Ϯ SD) of representative spleens from such BOCs, quantifying the subpopulations indicated, after immunization with NP-Ficoll. Chimeric percentages indicate the percentage of CD45.2-staining cells of the subpopulations indicated. b Significant differences between wild-type (W/T) and knockout (K/O) donor cohorts ( p Ͻ 0.001). Ig␭ IgGs, and anti-hapten responses using NP-BSA and TNP-BSA, were Table I . The PCR products were cloned into pCR2.1-TOPO (Invitrogen performed as described (4, 12). Germinal centers were identified by stain- Life Technologies), and their sequence was determined by routine ing frozen spleen sections with peanut agglutinin (PNA)-FITC, as previ- sequencing. ously described (4). Results In vitro B cell studies Spontaneous high-affinity autoantibodies in Foxj1 deficiency B cell purification and stimulation was performed similarly to a previous Downloaded from study (13).
Load more

Recommended publications
  • Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
    The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells.
    [Show full text]
  • Deciphering the Nature of Trp73 Isoforms in Mouse
    cancers Article Deciphering the Nature of Trp73 Isoforms in Mouse Embryonic Stem Cell Models: Generation of Isoform-Specific Deficient Cell Lines Using the CRISPR/Cas9 Gene Editing System Lorena López-Ferreras 1,2,†, Nicole Martínez-García 1,3,†, Laura Maeso-Alonso 1,2,‡, Marta Martín-López 1,4,‡, Ángela Díez-Matilla 1,‡ , Javier Villoch-Fernandez 1,2, Hugo Alonso-Olivares 1,2, Margarita M. Marques 3,5,* and Maria C. Marin 1,2,* 1 Instituto de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain; [email protected] (L.L.-F.); [email protected] (N.M.-G.); [email protected] (L.M.-A.); [email protected] (M.M.-L.); [email protected] (Á.D.-M.); [email protected] (J.V.-F.); [email protected] (H.A.-O.) 2 Departamento de Biología Molecular, Universidad de León, 24071 León, Spain 3 Departamento de Producción Animal, Universidad de León, 24071 León, Spain 4 Biomar Microbial Technologies, Parque Tecnológico de León, Armunia, 24009 León, Spain 5 Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, 24071 León, Spain * Correspondence: [email protected] (M.M.M.); [email protected] (M.C.M.); Tel.: +34-987-291757 Citation: López-Ferreras, L.; (M.M.M.); +34-987-291490 (M.C.M.) Martínez-García, N.; Maeso-Alonso, † Equal contribution. ‡ Equal contribution. L.; Martín-López, M.; Díez-Matilla, Á.; Villoch-Fernandez, J.; Simple Summary: The Trp73 gene is involved in the regulation of multiple biological processes Alonso-Olivares, H.; Marques, M.M.; Marin, M.C. Deciphering the Nature such as response to stress, differentiation and tissue architecture.
    [Show full text]
  • Ten Commandments for a Good Scientist
    Unravelling the mechanism of differential biological responses induced by food-borne xeno- and phyto-estrogenic compounds Ana María Sotoca Covaleda Wageningen 2010 Thesis committee Thesis supervisors Prof. dr. ir. Ivonne M.C.M. Rietjens Professor of Toxicology Wageningen University Prof. dr. Albertinka J. Murk Personal chair at the sub-department of Toxicology Wageningen University Thesis co-supervisor Dr. ir. Jacques J.M. Vervoort Associate professor at the Laboratory of Biochemistry Wageningen University Other members Prof. dr. Michael R. Muller, Wageningen University Prof. dr. ir. Huub F.J. Savelkoul, Wageningen University Prof. dr. Everardus J. van Zoelen, Radboud University Nijmegen Dr. ir. Toine F.H. Bovee, RIKILT, Wageningen This research was conducted under the auspices of the Graduate School VLAG Unravelling the mechanism of differential biological responses induced by food-borne xeno- and phyto-estrogenic compounds Ana María Sotoca Covaleda Thesis submitted in fulfillment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. dr. M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Tuesday 14 September 2010 at 4 p.m. in the Aula Unravelling the mechanism of differential biological responses induced by food-borne xeno- and phyto-estrogenic compounds. Ana María Sotoca Covaleda Thesis Wageningen University, Wageningen, The Netherlands, 2010, With references, and with summary in Dutch. ISBN: 978-90-8585-707-5 “Caminante no hay camino, se hace camino al andar. Al andar se hace camino, y al volver la vista atrás se ve la senda que nunca se ha de volver a pisar” - Antonio Machado – A mi madre.
    [Show full text]
  • Chloride Channels Regulate Differentiation and Barrier Functions
    RESEARCH ARTICLE Chloride channels regulate differentiation and barrier functions of the mammalian airway Mu He1†*, Bing Wu2†, Wenlei Ye1, Daniel D Le2, Adriane W Sinclair3,4, Valeria Padovano5, Yuzhang Chen6, Ke-Xin Li1, Rene Sit2, Michelle Tan2, Michael J Caplan5, Norma Neff2, Yuh Nung Jan1,7,8, Spyros Darmanis2*, Lily Yeh Jan1,7,8* 1Department of Physiology, University of California, San Francisco, San Francisco, United States; 2Chan Zuckerberg Biohub, San Francisco, United States; 3Department of Urology, University of California, San Francisco, San Francisco, United States; 4Division of Pediatric Urology, University of California, San Francisco, Benioff Children’s Hospital, San Francisco, United States; 5Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Heaven, United States; 6Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, United States; 7Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; 8Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States *For correspondence: Abstract The conducting airway forms a protective mucosal barrier and is the primary target of [email protected] (MH); [email protected] airway disorders. The molecular events required for the formation and function of the airway (SD); mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway [email protected] (LYJ) diseases,
    [Show full text]
  • KRAS Drives Immune Evasion in a Genetic Model of Pancreatic Cancer
    ARTICLE https://doi.org/10.1038/s41467-021-21736-w OPEN KRAS drives immune evasion in a genetic model of pancreatic cancer Irene Ischenko1, Stephen D’Amico1, Manisha Rao2, Jinyu Li2, Michael J. Hayman1, Scott Powers 2, ✉ ✉ Oleksi Petrenko 1,3 & Nancy C. Reich 1,3 Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate 1234567890():,; KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the sup- pression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment. 1 Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA. 2 Department of Pathology, Stony Brook University, ✉ Stony Brook, NY, USA. 3These authors jointly supervised this work: Oleksi Petrenko, Nancy C. Reich. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2021) 12:1482 | https://doi.org/10.1038/s41467-021-21736-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21736-w RAS is frequently associated with some of the deadliest and characterization of KRASG12D p53KO mouse cell lines forms of cancer.
    [Show full text]
  • Rb Family Proteins Differentially Regulate Distinct Cell Lineages During Epithelial Development Kathryn A
    Research article 4299 Rb family proteins differentially regulate distinct cell lineages during epithelial development Kathryn A. Wikenheiser-Brokamp Department of Pathology and Immunology, and Division of Molecular Oncology in the Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA e-mail: [email protected] Accepted 23 April 2004 Development 131, 4299-4310 Published by The Company of Biologists 2004 doi:10.1242/dev.01232 Summary pRb, p107 and p130 are important regulators of cell cycle cell types. Ablation of total Rb family function resulted and have extensive overlapping functions; however, only in opposing effects in specification along distinct cell Rb has been shown to be a bone fide tumor suppressor. lineages, providing evidence that pocket proteins inhibit Defining the overlapping versus distinct pocket protein neuroendocrine cell fate while being required for functions is therefore an important step to understanding differentiation in other cell types. These findings identify a the unique role of Rb. Using lung as a model, the present novel role for pocket proteins in cell fate determination, studies demonstrate that pocket proteins are important not and establish a unique cell lineage-specific function for Rb only in regulating cell cycle and survival but also in cell that explains, at least in part, why Rb and p16 are lineage specification. An inducible lung-specific Rb inactivated in phenotypically distinct carcinomas. knockout strategy was used to demonstrate that Rb is specifically required for restricting neuroendocrine cell fate Key words: Rb, p107, p130, Cre-LoxP system, Lung development, despite functional compensation for Rb deficiency in other CC10 Introduction overexpressed (Classon and Dyson, 2001; Harbour and Dean, The retinoblastoma protein (Rb) is a prototype tumor 2000).
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Specification of a Foxj1-Dependent Lineage in the Forebrain Is Required for Embryonic-To-Postnatal Transition of Neurogenesis in the Olfactory Bulb
    9368 • The Journal of Neuroscience, June 22, 2011 • 31(25):9368–9382 Development/Plasticity/Repair Specification of a Foxj1-Dependent Lineage in the Forebrain Is Required for Embryonic-to-Postnatal Transition of Neurogenesis in the Olfactory Bulb Benoit V. Jacquet,1 Nagendran Muthusamy,1 Laura J. Sommerville,1 Guanxi Xiao,1 Huixuan Liang,1 Yong Zhang,2 Michael J. Holtzman,2 and H. Troy Ghashghaei1 1Center for Comparative Medicine and Translational Research, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, and 2Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110 Establishment of a neural stem cell niche in the postnatal subependymal zone (SEZ) and the rostral migratory stream (RMS) is required for postnatal and adult neurogenesis in the olfactory bulbs (OB). We report the discovery of a cellular lineage in the SEZ-RMS-OB continuum, the specification of which is dependent on the expression of the forkhead transcription factor Foxj1 in mice. Spatially and temporally restricted Foxj1ϩ neuronal progenitors emerge during embryonic periods, surge during perinatal development, and are active only for the first few postnatal weeks. We show that the development of the unique Foxj1-derived lineage is dependent on Foxj1 expression and is required for overall postnatal neurogenesis in the OB. Strikingly, the production of neurons from Foxj1ϩ progenitors significantly declines after the early postnatal weeks, but Foxj1-derived neurons in the OB persist during adult periods. For the first time, our study identifies the time- and region-specific activity of a perinatal progenitor domain that is required for transition and progression of OB neurogenesis from the embryonic-to-postnatal periods.
    [Show full text]
  • The Expression of Genes Contributing to Pancreatic Adenocarcinoma Progression Is Influenced by the Respective Environment – Sagini Et Al
    The expression of genes contributing to pancreatic adenocarcinoma progression is influenced by the respective environment – Sagini et al Supplementary Figure 1: Target genes regulated by TGM2. Figure represents 24 genes regulated by TGM2, which were obtained from Ingenuity Pathway Analysis. As indicated, 9 genes (marked red) are down-regulated by TGM2. On the contrary, 15 genes (marked red) are up-regulated by TGM2. Supplementary Table 1: Functional annotations of genes from Suit2-007 cells growing in pancreatic environment Categoriesa Diseases or p-Valuec Predicted Activation Number of genesf Functions activationd Z-scoree Annotationb Cell movement Cell movement 1,56E-11 increased 2,199 LAMB3, CEACAM6, CCL20, AGR2, MUC1, CXCL1, LAMA3, LCN2, COL17A1, CXCL8, AIF1, MMP7, CEMIP, JUP, SOD2, S100A4, PDGFA, NDRG1, SGK1, IGFBP3, DDR1, IL1A, CDKN1A, NREP, SEMA3E SERPINA3, SDC4, ALPP, CX3CL1, NFKBIA, ANXA3, CDH1, CDCP1, CRYAB, TUBB2B, FOXQ1, SLPI, F3, GRINA, ITGA2, ARPIN/C15orf38- AP3S2, SPTLC1, IL10, TSC22D3, LAMC2, TCAF1, CDH3, MX1, LEP, ZC3H12A, PMP22, IL32, FAM83H, EFNA1, PATJ, CEBPB, SERPINA5, PTK6, EPHB6, JUND, TNFSF14, ERBB3, TNFRSF25, FCAR, CXCL16, HLA-A, CEACAM1, FAT1, AHR, CSF2RA, CLDN7, MAPK13, FERMT1, TCAF2, MST1R, CD99, PTP4A2, PHLDA1, DEFB1, RHOB, TNFSF15, CD44, CSF2, SERPINB5, TGM2, SRC, ITGA6, TNC, HNRNPA2B1, RHOD, SKI, KISS1, TACSTD2, GNAI2, CXCL2, NFKB2, TAGLN2, TNF, CD74, PTPRK, STAT3, ARHGAP21, VEGFA, MYH9, SAA1, F11R, PDCD4, IQGAP1, DCN, MAPK8IP3, STC1, ADAM15, LTBP2, HOOK1, CST3, EPHA1, TIMP2, LPAR2, CORO1A, CLDN3, MYO1C,
    [Show full text]
  • BMP Signaling Suppresses Gemc1 Expression and Ependymal
    www.nature.com/scientificreports OPEN BMP signaling suppresses Gemc1 expression and ependymal diferentiation of mouse telencephalic progenitors Hanae Omiya1, Shima Yamaguchi1, Tomoyuki Watanabe1, Takaaki Kuniya1, Yujin Harada1, Daichi Kawaguchi1* & Yukiko Gotoh1,2* The lateral ventricles of the adult mammalian brain are lined by a single layer of multiciliated ependymal cells, which generate a fow of cerebrospinal fuid through directional beating of their cilia as well as regulate neurogenesis through interaction with adult neural stem cells. Ependymal cells are derived from a subset of embryonic neural stem-progenitor cells (NPCs, also known as radial glial cells) that becomes postmitotic during the late embryonic stage of development. Members of the Geminin family of transcriptional regulators including GemC1 and Mcidas play key roles in the diferentiation of ependymal cells, but it remains largely unclear what extracellular signals regulate these factors and ependymal diferentiation during embryonic and early-postnatal development. We now show that the levels of Smad1/5/8 phosphorylation and Id1/4 protein expression—both of which are downstream events of bone morphogenetic protein (BMP) signaling—decline in cells of the ventricular- subventricular zone in the mouse lateral ganglionic eminence in association with ependymal diferentiation. Exposure of postnatal NPC cultures to BMP ligands or to a BMP receptor inhibitor suppressed and promoted the emergence of multiciliated ependymal cells, respectively. Moreover, treatment of embryonic NPC cultures with BMP ligands reduced the expression level of the ependymal marker Foxj1 and suppressed the emergence of ependymal-like cells. Finally, BMP ligands reduced the expression levels of Gemc1 and Mcidas in postnatal NPC cultures, whereas the BMP receptor inhibitor increased them.
    [Show full text]
  • Reconstruction and Analysis of Transcriptional Regulatory Networks with Trena
    Reconstruction and Analysis of Transcriptional Regulatory Networks with TReNA Seth A. Ament Institute for Systems Biology Seattle, Washington Genes influence phenotypes through a network of networks Social Network Brain Connectivity Network Individual Neuronal Network Molecular Network DNA Transcriptional Regulatory Network Analysis (TReNA) Sequence Motifs DNase footprints Epigenomic States Evolutionary Conservation JASPAR ENCODE ROADMAP/FANTOM phastCons FootprintFinder Tissue-Specific TF Binding Sites Software Availability: https://github.com/PriceLab/TReNA Transcriptional Regulatory Network Analysis (TReNA) Sequence Motifs DNase footprints Epigenomic States Evolutionary Conservation JASPAR ENCODE ROADMAP/FANTOM phastCons FootprintFinder Tissue-Specific Tissue-Specific Transcriptome Profiles TF Binding Sites GTEx/GEO fitTRN Tissue-Specific Transcriptional Regulatory Network (TF-Target Gene Interactions) Software Availability: https://github.com/PriceLab/TReNA Combining diverse annotations improves prediction of TF binding sites 1.0 TRUE/FALSE classes: USF1 DNase footprints with/without USF1 ChIP-seq 0.8 peaks 0.6 All USF1 footprints: 79% sensitivity Sensitivity 31% specificity 0.4 USF1 footprints with 0.2 modeled probability > 50%: FIMO + Wellington + ChromHMM + phastCons 55% sensitivity FIMO p−value 70% specificity Wellington p−value 0.0 1.0 0.8 0.6 0.4 0.2 0.0 Specificity Combining TF binding sites and gene co-expression improves prediction of TFs’ functional target genes Co-Expression TF Binding Sites Ensemble 1.0 0.8 *** *** 0.6 OC
    [Show full text]
  • Sex Steroid Hormone Receptors in the Developing Female Reproductive Tract of Laboratory Rodents
    The Journal of Toxicological Sciences, Review 75 Vol.30, No.2, 75-89, 2005 SEX STEROID HORMONE RECEPTORS IN THE DEVELOPING FEMALE REPRODUCTIVE TRACT OF LABORATORY RODENTS Akinobu OKADA1*, Tomomi SATO2,YasuhikoOHTA3, 4 andTaisenIGUCHI4, 5 1Safety Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 1-1-8 Azusawa, Itabashi-ku, Tokyo 174-8511, Japan 2Graduate School of Integrated Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan 3Department of Veterinary Science, Faculty of Agriculture, Tottori University, 4-104 Koyama-Minami, Tottori 680-8553, Japan 4CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi 332-0012, Japan 5Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Science, and Department of Molecular Biomechanics, School of Life Science, The Graduate University for Advanced Studies, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan (Received January 7, 2005; Accepted February 8, 2005) ABSTRACT — Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans. Some of these chemicals exhibit estrogenic activity by binding to the estrogen receptors. The developing organism is particularly sensitive to estrogenic chemicals during the critical period in which the induction of long-term changes and persistent molecular alterations in female repro- ductive tracts occur. Perinatal mouse and rat models can be utilized as indicators for determining the con- sequences of exposure to exogenous estrogenic agents, including possible xenoestrogens or environmental endocrine disruptors. Estrogen receptors (ER) and estrogen responsive genes, therefore, need to be iden- tified in order to understand the molecular basis of estrogenic actions.
    [Show full text]