DOCSLIB.ORG

Foxn1 Maintains Thymic Epithelial Cells to Support T-Cell Development Via Mcm2 in Zebra Fish

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Foxn1 Maintains Thymic Epithelial Cells to Support T-Cell Development Via Mcm2 in Zebra Fish Foxn1 maintains thymic epithelial cells to support T-cell development via mcm2 in zebrafish Dongyuan Ma1, Lu Wang1, Sifeng Wang1, Ya Gao, Yonglong Wei, and Feng Liu2 State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China Edited by Max D. Cooper, Emory University, Atlanta, GA, and approved November 7, 2012 (received for review September 30, 2012) The thymus is mainly comprised of thymic epithelial cells (TECs), for the specification of lymphoid progenitors toward the T-cell which form the unique thymic epithelial microenvironment essential lineage (18, 19). However, other Foxn1-regulated downstream for intrathymic T-cell development. Foxn1, a member of the forkhead target genes have not yet been reported. transcription factor family, is required for establishing a functional To investigate the function of foxn1 during the development of thymic rudiment. However, the molecular mechanisms underlying thymus and T cells, we have used the zebrafish model to knock the function of Foxn1 are still largely unclear. Here, we show that down foxn1 expression by using antisense morpholinos (MO). Foxn1 functions in thymus development through Mcm2 in the Our data show that foxn1-deficient embryos display impaired zebrafish. We demonstrate that, in foxn1 knockdown embryos, expression of T-cell markers, whereas the expression of early TEC the thymic rudiment is reduced and T-cell development is im- progenitor markers remains relatively unchanged. Expression pro- paired. Genome-wide expression profiling shows that a number filing and functional analysis demonstrate that, besides the pre- of genes, including some known thymopoiesis genes, are dys- viously reported downstream target genes (such as ccl25) in medaka regulated during the initiation of the thymus primordium and and mice, a unique foxn1-mcm2 axis plays a pivotal role during immigration of T-cell progenitors to the thymus. Functional and the development of TECs and T cells in zebrafish. epistatic studies show that mcm2 and cdca7 are downstream of Foxn1, and mcm2 is a direct target gene of Foxn1 in TECs. Finally, Results we find that the thymus defects in foxn1 and mcm2 morphants T-Cell Development Is Impaired in Zebrafish foxn1 Morphants. Foxn1 might be attributed to reduced cell proliferation rather than apo- has been demonstrated to be necessary in thymopoiesis in many ptosis. Our results reveal that the foxn1-mcm2 axis plays a cen- vertebrates (9, 11, 16). To study the role of zebrafish Foxn1, tral role in the genetic regulatory network controlling thymus antisense MOs (16) were used to knock down the expression of development in zebrafish. foxn1 in zebrafish embryos. Then, whole mount in situ hybrid- ization (WISH) and Western blotting were carried out to check he thymus is a central hematopoietic organ that produces ma- the endogenous expression of zebrafish foxn1 mRNA and the Tture T lymphocytes, one of the major players of the vertebrate encoded protein Foxn1. We found that both the levels of foxn1 adaptive immune system (1). In vertebrates, including zebrafish and mRNA and Foxn1 protein were down-regulated in the zebrafish mice, the thymus primordium is derived from the third pharyngeal embryos injected with 4 ng of foxn1 MOs (Fig. 1 A and B). When endodermal pouch and then differentiates into functional cortical foxn1 MOs were injected into a rag2:dsRed transgenic line at the + and medullary thymic epithelial cells (TECs) (1–4). TECs repre- one cell stage, the numbers of the dsRed T cells were signif- sent the primary functional cell type that forms the unique thymic icantly decreased at 5 dpf (Fig. 1C). Compared with the control, epithelial microenvironment supporting T-cell differentiation. the expression of several T-cell markers including rag1, il7r, and Therefore, the thymic epithelial microenvironment must be tightly ikaros was remarkably decreased in the thymus of zebrafish foxn1 controlled by extrinsic signals and intrinsic factors to support morphants at 4 dpf (Fig. 1D). Quantitative RT-PCR (qPCR) fur- T-cell differentiation and maturation (5). Several signaling path- ther confirmed the WISH data (Fig. 1E). Moreover, when foxn1 ways and transcription factors have been demonstrated in thymus was knocked down in a cmyb:GFP transgenic line, the population + and T-cell development during vertebrate embryogenesis (4, 6–10). of the GFP T cells in the thymus was greatly reduced, whereas + Foxn1, Forkhead box protein N1, a winged-helix forkhead the numbers of the GFP hematopoietic progenitors in the pro- transcription factor, occupies a central position in the genetic nephros (the equivalent of bone marrow in mammals) and caudal network(s) that establishes a functional thymic rudiment (9, 11, 12). hematopoietic tissue (the equivalent of fetal liver in mammals) at − − Foxn1 / mice are athymic and hairless (9). Hypomorphic allele 4 dpf were not changed in foxn1 morphants (Fig. S1A) (20). In studies have suggested that Foxn1 is required for TEC development addition, a parathyroid marker, gcm2, was unchanged in foxn1 in both fetal and adult thymus in a dosage-dependent manner morphants (Fig. S1B). These results suggest a role for foxn1 in (13, 14). Conversely, overexpression of foxn1 can improve the thymus, which is consistent with data in mice. Moreover, epcam, reduction in the populations of thymocytes and TECs in aged and hoxa3a, appeared unchanged in foxn1 morphants (Fig. S2A). mice, therefore delaying age-associated thymic involution (15). These data are consistent with the observation that these genes The expression of zebrafish foxn1 is initiated in the thymic pri- act earlier than foxn1 during thymus development in mouse (5, 10). mordium approximately 48 h after fertilization (hpf) and then Previous work showed that thymus homing was defective in zebra- gradually increases with the immigration of T-cell progenitors fish foxn1 morphants because of the down-regulation of chemokine/ marked by rag1 and ikaros (3, 4). Moreover, knockdown of the chemokine receptors (16). Here, expression of chemokine and expression of foxn1 in zebrafish embryos using antisense morpho- linos impairs T-cell development (16). Despite the essential function of foxn1 in the early develop- Author contributions: D.M. and F.L. designed research; D.M., L.W., S.W., Y.G., and Y.W. ment of the thymus, there is limited understanding of its down- performed research; D.M., L.W., and F.L. analyzed data; and F.L. wrote the paper. stream targets and detailed regulatory mechanisms remain elusive. The authors declare no conflict of interest. For example, previous studies have shown that dll4 and chemokine This article is a PNAS Direct Submission. ligand ccl25 might be directly regulated by Foxn1 in mice and 1D.M., L.W., and S.W. contributed equally to this work. medaka (16). Chemokine signaling pathways (ccl25/ccr9, cxcl12/ 2To whom correspondence should be addressed. E-mail: [email protected]. cxcr4) are thought to be important for attracting lymphoid pro- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. genitors (17), whereas the Notch pathway (dll4/notch1) is required 1073/pnas.1217021110/-/DCSupplemental. 21040–21045 | PNAS | December 18, 2012 | vol. 109 | no. 51 www.pnas.org/cgi/doi/10.1073/pnas.1217021110 Downloaded by guest on September 28, 2021 Fig. 1. T-cell development is impaired in zebrafish foxn1 morphants. (A and B) The endogenous expression level of foxn1 transcript and the encoded protein in zebrafish foxn1 morphants at 4 dpf detected by WISH (A) and Western blot (B). Ba, Western blot; Bb, Western blot results were quantified by using Quantity 1 software. (C) The rag2:dsRed expression was abolished in foxn1 morphants at 5 dpf. (D) The expression of lymphocyte markers, including rag1, il7r, and ikaros, was down-regulated in the thymus in zebrafish foxn1 morphants. Anterior to the left and dorsal to the top; circles mark the thymus. (E) qRT-PCR results showing that the expression of rag1, il7r, and ikaros is down-regulated in zebrafish foxn1 morphants (mean ± SD, t test, **P < 0.01, n = 3). IMMUNOLOGY chemokine receptor was also examined. We found that the ex- and Cbfb have been reported to be expressed in mouse T lym- pression of ccr9b and ccl25a was both decreased in foxn1 mor- phocytes (25, 26). The detailed expression pattern of these four phants at 4 dpf (Fig. S2B). Taken together, knockdown of foxn1 genes in zebrafish was examined by using WISH in cloche mu- expression impairs T-cell development in zebrafish embryos. tant, which contains no blood including lymphoid cells, although a few TECs still exist according to the expression of foxn1 (Fig. Expression of mcm2, cdca7, cbfb, and runx3 Is Specifically Down- S4A). Our results show that the absence of runx3 and reduced Regulated in the Thymus of Zebrafish foxn1 Morphants. Although cbfb expression was detected in the thymus, whereas cdca7 and foxn1 is pivotal in establishing a functional thymic rudiment, there mcm2 were still expressed in the thymus of the cloche mutant at is limited understanding of its downstream targets. To further 4 dpf (Fig. S4A). Transverse sections of WISH embryos at 4 dpf study the molecular mechanism of foxn1 in thymopoiesis, micro- clearly demonstrated their expression in the thymus was reduced array experiments were carried out. Zebrafish thymus collected in foxn1 morphants compared with controls (Fig. S4B). To de- at two stages, 2 dpf and 4 dpf, were analyzed because the thymic termine whether these genes were also expressed in TECs and/or anlage forms from the pharyngeal endoderm at 2 dpf and lym- T cells in mammals, we examined their expression in mouse thymus phopoiesis initiates after the expression of rag1 at 4 dpf. According tissue and TEC lines. By RT-PCR, expression of cdca7 and mcm2 to the microarray data, 310 genes were up-regulated, whereas but not runx3 was detected in two mouse TEC lines, 4c18 and 1c6, 466 genes were down-regulated at 2 dpf, and 379 genes were whereas all four genes were expressed in mouse thymus tissue up-regulated, whereas 369 genes were down-regulated at 4 dpf (Fig.
Load more

Recommended publications
  • FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Archivio della ricerca - Università degli studi di Napoli Federico II J Clin Immunol DOI 10.1007/s10875-017-0445-z CME REVIEW FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches Vera Gallo1 & Emilia Cirillo1 & Giuliana Giardino1 & Claudio Pignata1 Received: 29 June 2017 /Accepted: 11 September 2017 # Springer Science+Business Media, LLC 2017 Abstract Since the discovery of FOXN1 deficiency, the hu- cellular and humoral immunity. To date, more than 20 genetic man counterpart of the nude mouse, a growing body of evi- alterations have been identified as responsible for the disease dence investigating the role of FOXN1 in thymus and skin, [1]. Among these, the FOXN1 gene mutation, causative of the has been published. FOXN1 has emerged as fundamental for nude SCID phenotype, is the unique condition in which the thymus development, function, and homeostasis, representing immunological defect is related to an alteration of the thymic the master regulator of thymic epithelial and T cell develop- epithelial stroma and not to an intrinsic defect of the hemato- ment. In the skin, it also plays a pivotal role in keratinocytes poietic cell. The nude SCID phenotype has been identified in and hair follicle cell differentiation, although the underlying human for the first time in 1996 in two female patients who molecular mechanisms still remain to be fully elucidated. The presented with thymus aplasia and ectodermal abnormalities nude severe combined immunodeficiency phenotype is in- [2], approximately 30 years later than the initial description of deed characterized by the clinical hallmarks of athymia with the murine counterpart.
    [Show full text]
  • The Myc Target Gene JPO1/CDCA7 Is Frequently Overexpressed in Human Tumors and Has Limited Transforming Activity in Vivo
    Research Article The Myc Target Gene JPO1/CDCA7 Is Frequently Overexpressed in Human Tumors and Has Limited Transforming Activity In vivo Rebecca C. Osthus,1,2 Baktiar Karim,5 Julia E. Prescott,1 B. Douglas Smith,6 Michael McDevitt,2,6 David L. Huso,5 and Chi V. Dang1,2,3,4,6 1Program in Human Genetics and Molecular Biology, 2Division of Hematology, 3Departments of Medicine, Cell Biology, 4Pathology, and 5Comparative Medicine, 6The Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland Abstract metabolism, ribosome biogenesis as well as other cellular processes, how deregulated MYC expression contributes to MYC is frequently overexpressed in human cancers, but the downstream events contributing to tumorigenesis remain tumorigenesis through targets genes remains poorly understood. incompletely understood. MYC encodes an oncogenic tran- In particular, the contributions of large numbers of target genes scription factor, of which target genes presumably contribute with unknown functions to Myc-mediated tumorigenesis remain to cellular transformation. Although Myc regulates about 15% undelineated. Here, we sought to determine the expression pattern of genes and combinations of target genes are likely required of JPO1/CDCA7, which encodes a nuclear protein with unknown for tumorigenesis, we studied in depth the expression of the function, in human cancers and its transforming activity in Myc target gene, JPO1/CDCA7, in human cancers and its ability transgenic mice. to provoke tumorigenesis in transgenic mice. JPO1/CDCA7 is We identified JPO1 as a novel transcript that is differentially regulated in Myc-transformed fibroblasts in a representational frequently overexpressed in human cancers, and in particular, difference analysis screen (13).
    [Show full text]
  • Supplementary Data
    SUPPLEMENTARY DATA A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma Santiago Demajo et al. 1 SUPPLEMENTARY DATA INDEX Supplementary Methods p. 3 Supplementary References p. 8 Supplementary Tables (S1 to S5) p. 9 Supplementary Figures (S1 to S15) p. 17 2 SUPPLEMENTARY METHODS Western blot, immunoprecipitation, and qRT-PCR Western blot (WB) analysis was performed as previously described (1), using cyclin D1 (Santa Cruz Biotechnology, sc-753, RRID:AB_2070433) and tubulin (Sigma-Aldrich, T5168, RRID:AB_477579) antibodies. Co-immunoprecipitation assays were performed as described before (2), using cyclin D1 antibody (Santa Cruz Biotechnology, sc-8396, RRID:AB_627344) or control IgG (Santa Cruz Biotechnology, sc-2025, RRID:AB_737182) followed by protein G- magnetic beads (Invitrogen) incubation and elution with Glycine 100mM pH=2.5. Co-IP experiments were performed within five weeks after cell thawing. Cyclin D1 (Santa Cruz Biotechnology, sc-753), E2F4 (Bethyl, A302-134A, RRID:AB_1720353), FOXM1 (Santa Cruz Biotechnology, sc-502, RRID:AB_631523), and CBP (Santa Cruz Biotechnology, sc-7300, RRID:AB_626817) antibodies were used for WB detection. In figure 1A and supplementary figure S2A, the same blot was probed with cyclin D1 and tubulin antibodies by cutting the membrane. In figure 2H, cyclin D1 and CBP blots correspond to the same membrane while E2F4 and FOXM1 blots correspond to an independent membrane. Image acquisition was performed with ImageQuant LAS 4000 mini (GE Healthcare). Image processing and quantification were performed with Multi Gauge software (Fujifilm). For qRT-PCR analysis, cDNA was generated from 1 µg RNA with qScript cDNA Synthesis kit (Quantabio). qRT–PCR reaction was performed using SYBR green (Roche).
    [Show full text]
  • Supplementary Table 1. Pain and PTSS Associated Genes (N = 604
    Supplementary Table 1. Pain and PTSS associated genes (n = 604) compiled from three established pain gene databases (PainNetworks,[61] Algynomics,[52] and PainGenes[42]) and one PTSS gene database (PTSDgene[88]). These genes were used in in silico analyses aimed at identifying miRNA that are predicted to preferentially target this list genes vs. a random set of genes (of the same length). ABCC4 ACE2 ACHE ACPP ACSL1 ADAM11 ADAMTS5 ADCY5 ADCYAP1 ADCYAP1R1 ADM ADORA2A ADORA2B ADRA1A ADRA1B ADRA1D ADRA2A ADRA2C ADRB1 ADRB2 ADRB3 ADRBK1 ADRBK2 AGTR2 ALOX12 ANO1 ANO3 APOE APP AQP1 AQP4 ARL5B ARRB1 ARRB2 ASIC1 ASIC2 ATF1 ATF3 ATF6B ATP1A1 ATP1B3 ATP2B1 ATP6V1A ATP6V1B2 ATP6V1G2 AVPR1A AVPR2 BACE1 BAMBI BDKRB2 BDNF BHLHE22 BTG2 CA8 CACNA1A CACNA1B CACNA1C CACNA1E CACNA1G CACNA1H CACNA2D1 CACNA2D2 CACNA2D3 CACNB3 CACNG2 CALB1 CALCRL CALM2 CAMK2A CAMK2B CAMK4 CAT CCK CCKAR CCKBR CCL2 CCL3 CCL4 CCR1 CCR7 CD274 CD38 CD4 CD40 CDH11 CDK5 CDK5R1 CDKN1A CHRM1 CHRM2 CHRM3 CHRM5 CHRNA5 CHRNA7 CHRNB2 CHRNB4 CHUK CLCN6 CLOCK CNGA3 CNR1 COL11A2 COL9A1 COMT COQ10A CPN1 CPS1 CREB1 CRH CRHBP CRHR1 CRHR2 CRIP2 CRYAA CSF2 CSF2RB CSK CSMD1 CSNK1A1 CSNK1E CTSB CTSS CX3CL1 CXCL5 CXCR3 CXCR4 CYBB CYP19A1 CYP2D6 CYP3A4 DAB1 DAO DBH DBI DICER1 DISC1 DLG2 DLG4 DPCR1 DPP4 DRD1 DRD2 DRD3 DRD4 DRGX DTNBP1 DUSP6 ECE2 EDN1 EDNRA EDNRB EFNB1 EFNB2 EGF EGFR EGR1 EGR3 ENPP2 EPB41L2 EPHB1 EPHB2 EPHB3 EPHB4 EPHB6 EPHX2 ERBB2 ERBB4 EREG ESR1 ESR2 ETV1 EZR F2R F2RL1 F2RL2 FAAH FAM19A4 FGF2 FKBP5 FLOT1 FMR1 FOS FOSB FOSL2 FOXN1 FRMPD4 FSTL1 FYN GABARAPL1 GABBR1 GABBR2 GABRA2 GABRA4
    [Show full text]
  • Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects Against Glioblastoma
    pharmaceutics Article Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma Laura Lucía Trebucq 1, Georgina Alexandra Cardama 2, Pablo Lorenzano Menna 2, Diego Andrés Golombek 1 , Juan José Chiesa 1,*,† and Luciano Marpegan 3,*,† 1 Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, Bernal 1876, Buenos Aires, Argentina; [email protected] (L.L.T.); [email protected] (D.A.G.) 2 Laboratorio de Oncología Molecular, Universidad Nacional de Quilmes-CONICET, Bernal 1876, Buenos Aires, Argentina; [email protected] (G.A.C.); [email protected] (P.L.M.) 3 Departamento de Física Médica, Comisión Nacional de Energía Atómica, Bariloche 8400, Río Negro, Argentina * Correspondence: [email protected] (J.J.C.); [email protected] (L.M.) † These authors contributed equally to this work. Abstract: The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human Citation: Trebucq, L.L.; glioblastoma cells and tumor-bearing nude mice. Methods. Wild-type LN229 and BMAL1-deficient Cardama, G.A.; Lorenzano Menna, P.; (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, Golombek, D.A.; Chiesa, J.J.; and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels.
    [Show full text]
  • This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G
    This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Investigation into the role of LSH ATPase in chromatin remodelling Alina Gukova Doctor of Philosophy – University of Edinburgh – 2020 ABSTRACT Chromatin remodelling is a crucial nuclear process affecting replication, transcription and repair. Global reduction of DNA methylation is observed in Immunodeficiency-Centromeric Instability-Facial Anomaly (ICF) syndrome. Several proteins were found to be mutated in patients diagnosed with ICF, among them are LSH and CDCA7. LSH is a chromatin remodeller bearing homology to the members of Sf2 remodelling family. A point mutation in its ATPase lobe was identified in ICF. CDCA7 is a zinc finger protein that was recently found to be crucial for nucleosome remodelling activity of LSH. Several point mutations in its zinc finger domain were described in ICF patients. In vitro and in vivo studies have shown that LSH-/- phenotype demonstrates reduction of global DNA methylation, implying that chromatin remodelling LSH functions may be required for the efficient methyltransferase activity, linking this finding to ICF phenotype.
    [Show full text]
  • Thymic Epithelial Progenitor Cells and Thymus Regeneration: an Update
    npg Progenitor cells and thymus regeneration 50 Cell Research (2007) 17: 50-55 npg © 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/07 $ 30.00 REVIEW www.nature.com/cr Thymic epithelial progenitor cells and thymus regeneration: an update Lianjun Zhang1,2, Liguang Sun1,3, Yong Zhao1 1Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zo- ology, 2Graduate University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100080, China; 3School of Public Health, Jilin University, Changchun 130021, China The thymus provides the essential microenvironment for T-cell development and maturation. Thymic epithelial cells (TECs), which are composed of thymic cortical epithelial cells (cTECs) and thymic medullary epithelial cells (mTECs), have been well documented to be critical for these tightly regulated processes. It has long been controversial whether the common progenitor cells of TECs could give rise to both cTECs and mTECs. Great progress has been made to charac- terize the common TEC progenitor cells in recent years. We herein discuss the sole origin paradigm with regard to TEC differentiation as well as these progenitor cells in thymus regeneration. Cell Research (2007) 17:50-55. doi:10.1038/sj.cr.7310114; published online 5 December 2006 Keywords: thymic epithelial progenitor cells, thymus organogenesis, thymus regeneration Introduction ling events still remain poorly understood [7-9]. Only the thymocytes recognizing major histocompatibility complex In general, stem cells are characterized by two funda- (MHC)-self peptide complexes in an appropriate avidity mental properties of self-renewal potential and further can survive the stringent positive and negative selections differentiation into several specialized cell types.
    [Show full text]
  • Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho Yan Xing, Michelle J
    Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho Yan Xing, Michelle J. Smith, Christine A. Goetz, Ron T. McElmurry, Sarah L. Parker, Dullei Min, Georg A. This information is current as Hollander, Kenneth I. Weinberg, Jakub Tolar, Heather E. of September 28, 2021. Stefanski and Bruce R. Blazar J Immunol published online 29 October 2018 http://www.jimmunol.org/content/early/2018/10/28/jimmun ol.1800670 Downloaded from 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 28, 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 29, 2018, doi:10.4049/jimmunol.1800670 The Journal of Immunology Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho Yan Xing,*,1 Michelle J. Smith,*,†,1 Christine A. Goetz,*,† Ron T. McElmurry,* Sarah L. Parker,* Dullei Min,‡ Georg A. Hollander,x,{ Kenneth I. Weinberg,‡ Jakub Tolar,* Heather E. Stefanski,*,2 and Bruce R.
    [Show full text]
  • (Foxn1-/-) Mice Affects the Skin Wound Healing Process Sylwia Ma
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.04.237388; this version posted August 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Impairment of the Hif-1α regulatory pathway in Foxn1-deficient (Foxn1-/-) mice affects the skin wound healing process Sylwia Machcinska, Marta Kopcewicz, Joanna Bukowska, Katarzyna Walendzik and Barbara Gawronska-Kozak* Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland * Correspondence: Barbara Gawronska-Kozak Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland; Tuwima 10; 10-748, Olsztyn, Poland; Tel: (4889) 5234634; Fax: (4889) 5240124. E-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.04.237388; this version posted August 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Hypoxia and hypoxia-regulated factors [e. g., hypoxia-inducible factor-1α (Hif-1α), factor inhibiting Hif-1α (Fih-1), thioredoxin-1 (Trx-1), aryl hydrocarbon receptor nuclear translocator 2 (Arnt-2)] have essential roles in skin wound healing. Using Foxn1-/- mice that can heal skin injuries in a unique scarless manner, we investigated the interaction between Foxn1 and hypoxia-regulated factors. The Foxn1-/- mice displayed impairments in the regulation of Hif-1α, Trx-1 and Fih-1 but not Arnt-2 during the healing process. An analysis of wounded skin showed that the skin of the Foxn1-/- mice healed in a scarless manner, displaying rapid re-epithelialization and an increase in transforming growth factor β (Tgfβ-3) and collagen III expression.
    [Show full text]
  • Role of the P63-Foxn1 Regulatory Axis in Thymic Epithelial Cell Homeostasis During Aging
    Citation: Cell Death and Disease (2013) 4, e932; doi:10.1038/cddis.2013.460 OPEN & 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13 www.nature.com/cddis Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging P Burnley1,3, M Rahman1,3, H Wang1,3, Z Zhang1, X Sun1, Q Zhuge2 and D-M Su*,1,2 The p63 gene regulates thymic epithelial cell (TEC) proliferation, whereas FoxN1 regulates their differentiation. However, their collaborative role in the regulation of TEC homeostasis during thymic aging is largely unknown. In murine models, the proportion of TAp63 þ , but not DNp63 þ , TECs was increased with age, which was associated with an age-related increase in senescent cell clusters, characterized by SA-b-Gal þ and p21 þ cells. Intrathymic infusion of exogenous TAp63 cDNA into young wild-type (WT) mice led to an increase in senescent cell clusters. Blockade of TEC differentiation via conditional FoxN1 gene knockout accelerated the appearance of this phenotype to early middle age, whereas intrathymic infusion of exogenous FoxN1 cDNA into aged WT mice brought only a modest reduction in the proportion of TAp63 þ TECs, but an increase in DNp63 þ TECs in the partially rejuvenated thymus. Meanwhile, we found that the increased TAp63 þ population contained a high proportion of phosphorylated-p53 TECs, which may be involved in the induction of cellular senescence. Thus, TAp63 levels are positively correlated with TEC senescence but inversely correlated with expression of FoxN1 and FoxN1-regulated TEC differentiation. Thereby, the p63-FoxN1 regulatory axis in regulation of postnatal TEC homeostasis has been revealed.
    [Show full text]
  • A Set of Regulatory Genes Co-Expressed in Embryonic Human Brain Is Implicated in Disrupted Speech Development
    Molecular Psychiatry https://doi.org/10.1038/s41380-018-0020-x ARTICLE A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development 1 1 1 2 3 Else Eising ● Amaia Carrion-Castillo ● Arianna Vino ● Edythe A. Strand ● Kathy J. Jakielski ● 4,5 6 7 8 9 Thomas S. Scerri ● Michael S. Hildebrand ● Richard Webster ● Alan Ma ● Bernard Mazoyer ● 1,10 4,5 6,11 6,12 13 Clyde Francks ● Melanie Bahlo ● Ingrid E. Scheffer ● Angela T. Morgan ● Lawrence D. Shriberg ● Simon E. Fisher 1,10 Received: 22 September 2017 / Revised: 3 December 2017 / Accepted: 2 January 2018 © The Author(s) 2018. This article is published with open access Abstract Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, CHD3 SETD1A WDR5 fi 1234567890();,: we discovered de novo mutations, implicating genes, including , and . In other probands, we identi ed novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.
    [Show full text]
  • Structural Basis of Specific DNA Binding by the Transcription Factor
    8388–8398 Nucleic Acids Research, 2019, Vol. 47, No. 16 Published online 21 June 2019 doi: 10.1093/nar/gkz557 Structural basis of specific DNA binding by the transcription factor ZBTB24 Ren Ren1,†, Swanand Hardikar1,†, John R. Horton1, Yue Lu1, Yang Zeng1,2,AnupK.Singh1, Kevin Lin1, Luis Della Coletta1, Jianjun Shen1,2, Celine Shuet Lin Kong3, Hideharu Hashimoto4, Xing Zhang1, Taiping Chen1,2,* and Xiaodong Cheng 1,2,* 1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 2 Houston, TX 77030, USA, Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Downloaded from https://academic.oup.com/nar/article/47/16/8388/5521786 by guest on 23 September 2021 Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA, 3Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA and 4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA Received October 13, 2018; Revised June 07, 2019; Editorial Decision June 11, 2019; Accepted June 13, 2019 ABSTRACT INTRODUCTION ZBTB24, encoding a protein of the ZBTB family ZBTB (zinc-finger- and BTB domain-containing) proteins, of transcriptional regulators, is one of four known characterized by the presence of an N-terminal BTB genes––the other three being DNMT3B, CDCA7 and (broad-complex, tram-track, and bric-a-brac)` domain [also HELLS––that are mutated in immunodeficiency, cen- known as POZ (poxvirus and zinc finger) domain] and a tromeric instability and facial anomalies (ICF) syn- C-terminal domain with tandem C2H2 Kr¨uppel-type zinc fingers (ZFs), are a large family of evolutionarily con- drome, a genetic disorder characterized by DNA hy- served transcriptional regulators (1).
    [Show full text]