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  • Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage
    1. Si Tao1,2,3,
    2. Duozhuang Tang1,
    3. Yohei Morita1,
    4. Tobias Sperka1,
    5. Omid Omrani1,
    6. André Lechel47,
    7. Vadim Sakk4,
    8. Johann Kraus5,
    9. Hans A Kestler1,5,
    10. Michael Kühl*,2 and
    11. Karl Lenhard Rudolph*,1,6
    1. 1Leibniz Institute for Age Research – Fritz Lipmann Institute e.V. (FLI), Jena, Germany
    2. 2Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
    3. 3International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm, Germany
    4. 4Cooperation Group between the Leibniz Institute for Age Research, Ulm University, Ulm, Germany
    5. 5Medical Systems Biology Unit, Ulm University, Ulm, Germany
    6. 6Research Group on Stem Cell Aging, Jena University Hospital (UKJ), Jena, Germany
    7. 7Department of Gastroenterology, University Hospital Ulm, Ulm, Germany
    1. * Corresponding author. Tel: +49 731 500 23283; Fax: +49 731 500 23277; E‐mail: michael.kuehl{at}uni-ulm.de

      Corresponding author. Tel: +49 3641 6563 50/52; Fax: +49 3641 6563 50/52; E‐mail: klrudolph{at}fli-leibniz.de

    New genetic results suggest that DNA damage‐induced modulation of Wnt signaling determines radio‐sensitivity of intestinal stem‐ and progenitor cells.

    Synopsis

    New genetic results suggest that DNA damage‐induced modulation of Wnt signaling determines radio‐sensitivity of intestinal stem‐ and progenitor cells.

    • Niche positioning‐associated Wnt signaling activity modulates sensitivity of intestinal stem and progenitor cells to DNA damage.

    • Wnt signaling enhances DNA damage responses in intestinal stem and progenitor cells.

    • Intestinal stem and progenitor cells with low Wnt activity preferentially survive in the context of DNA damage and telomere dysfunction.

    • Instructed enhancement of Wnt signaling increases radio‐sensitivity of intestinal stem and progenitor cells while inhibition of Wnt decreases it.

    • DNA damage
    • intestinal progenitor cells
    • intestinal stem cells
    • telomeres
    • Wnt
    • Received November 29, 2014.
    • Revision received December 22, 2014.
    • Accepted December 23, 2014.

    This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

    Si Tao, Duozhuang Tang, Yohei Morita, Tobias Sperka, Omid Omrani, André Lechel, Vadim Sakk, Johann Kraus, Hans A Kestler, Michael Kühl, Karl Lenhard Rudolph
  • The mRNA decay factor PAT1 functions in a pathway including MAP kinase 4 and immune receptor SUMM2
    1. Milena Edna Roux1,,
    2. Magnus Wohlfahrt Rasmussen1,,
    3. Kristoffer Palma2,
    4. Signe Lolle1,
    5. Àngels Mateu Regué1,
    6. Gerit Bethke3,
    7. Jane Glazebrook3,
    8. Weiping Zhang4,
    9. Leslie Sieburth4,
    10. Martin R Larsen5,
    11. John Mundy1 and
    12. Morten Petersen*,1
    1. 1Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
    2. 2New England Biolabs Ltd, Whitby, ON, Canada
    3. 3Department of Plant Biology, University of Minnesota, St. Paul, MN, USA
    4. 4Department of Biology, University of Utah, Salt Lake City, UT, USA
    5. 5University of Southern Denmark Institute for Biochemistry and Molecular Biology, Odense, Denmark
    1. *Corresponding author. Tel: +45 353 22127; E‐mail: shutko{at}bio.ku.dk
    1. These authors contributed equally to this work

    The identification of mRNA decapping factor PAT1 as a new target for MAP kinase 4 offers insight on the emerging connection between RNA metabolism and immunity in plants.

    Synopsis

    The identification of mRNA decapping factor PAT1 as a new target for MAP kinase 4 offers insight on the emerging connection between RNA metabolism and immunity in plants.

    • Eukaryotic PAT1 proteins are key components in post‐transcriptional regulation of gene expression

    • Arabidopsis PAT1 functions in decapping and is a substrate of MAP kinase 4 which regulates immune responses in a PAMP‐triggered pathway associated with the immune receptor SUMM2

    • PAT1 accumulates in processing (P) bodies upon PAMP treatment

    • PAT1 interacts with the resistance protein SUMM2 and pat1 mutants exhibit SUMM2‐dependent autoimmunity in Arabidopsis

    • decapping
    • immunity
    • MAP kinases
    • mRNA decay
    • phosphorylation
    • Received April 2, 2014.
    • Revision received December 2, 2014.
    • Accepted December 11, 2014.
    Milena Edna Roux, Magnus Wohlfahrt Rasmussen, Kristoffer Palma, Signe Lolle, Àngels Mateu Regué, Gerit Bethke, Jane Glazebrook, Weiping Zhang, Leslie Sieburth, Martin R Larsen, John Mundy, Morten Petersen
  • miR‐290/371‐Mbd2‐Myc circuit regulates glycolytic metabolism to promote pluripotency
    1. Yang Cao1,,
    2. Wen‐Ting Guo2,,
    3. Shengya Tian1,
    4. Xiaoping He1,
    5. Xi‐Wen Wang2,
    6. Xiaomeng Liu3,
    7. Kai‐Li Gu2,
    8. Xiaoyu Ma1,
    9. De Huang1,
    10. Lan Hu1,
    11. Yongping Cai4,
    12. Huafeng Zhang1,
    13. Yangming Wang*,2 and
    14. Ping Gao*,1
    1. 1The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Sciences, University of Science and Technology of China, Hefei, China
    2. 2Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking‐Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China
    3. 3Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing, China
    4. 4Department of Pathology, School of Medicine, Anhui Medical University, Hefei, China
    1. * Corresponding author. Tel: +86 10 62766945; E‐mail: yangming.wang{at}pku.edu.cn

      Corresponding author. Tel: +86 551 63607033; E‐mail: pgao2{at}ustc.edu.cn

    1. These authors contributed equally to this work

    New data reveal a miRNA‐Mbd2‐Myc network that directly controls metabolic enzymes to govern stem cell metabolism and pluripotency.

    Synopsis

    New data reveal a miRNA‐Mbd2‐Myc network that directly controls metabolic enzymes to govern stem cell metabolism and pluripotency.

    • miR‐290 cluster stimulates glycolytic metabolism to promote pluripotency.

    • miR‐290 cluster targets Mbd2 that represses glycolysis and reprogramming.

    • Mbd2 suppresses Myc that is critical for metabolic switch in ESCs.

    • miR‐371 cluster stimulates glycolysis to promote human somatic cell reprogramming.

    • glycolysis
    • microRNA
    • Mbd2
    • metabolism
    • pluripotency
    • Received October 30, 2014.
    • Revision received December 19, 2014.
    • Accepted December 23, 2014.
    Yang Cao, Wen‐Ting Guo, Shengya Tian, Xiaoping He, Xi‐Wen Wang, Xiaomeng Liu, Kai‐Li Gu, Xiaoyu Ma, De Huang, Lan Hu, Yongping Cai, Huafeng Zhang, Yangming Wang, Ping Gao
  • Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk
    1. Renuga Devi Rajaram15,
    2. Duje Buric1,
    3. Marian Caikovski1,
    4. Ayyakkannu Ayyanan1,
    5. Jacques Rougemont2,
    6. Jingdong Shan3,
    7. Seppo J Vainio3,
    8. Ozden Yalcin‐Ozuysal4 and
    9. Cathrin Brisken*,1
    1. 1Ecole Polytechnique Fédérale de Lausanne (EPFL) ISREC ‐ Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland
    2. 2Swiss Institute of Bioinformatics Bioinformatics and Biostatistics Core Facility Ecole polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
    3. 3Faculty of Biochemisty and Molecular Medicine (FBMM), Biocenter Oulu and Infotech Oulu Oulu Center for Cell Matrix Research University of Oulu, Oulu, Finland
    4. 4Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey
    5. 5Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
    1. *Corresponding author. Tel +41 21 693 07 81; +41 21 693 07 62; Fax +41 21 693 07 40; E‐mail: cathrin.brisken{at}epfl.ch

    This paper ascribes a new role for Wnt4 in pre‐pubertal mammary gland development while revealing luminal cells to respond to Wnt activation. During regeneration, Wnt4 interacts with progesterone receptor signaling, correcting previous notions on RANKL signaling in this context.

    Synopsis

    This paper ascribes a new role for Wnt4 in pre‐pubertal mammary gland development while revealing luminal cells to respond to Wnt activation. During regeneration, Wnt4 interacts with progesterone receptor signaling, correcting previous notions on RANKL signaling in this context.

    • Wnt4 is an essential control factor for mammary epithelial stem cell function.

    • RANKL is not required for mammary gland regeneration potential.

    • Wnt4 activates canonical Wnt signaling in the basal/myoepithelial compartment.

    • Progesterone receptor signaling is required for mammary epithelial Wnt4 expression already during puberty.

    • canonical Wnt signaling
    • hormones
    • mammary stem cells
    • myoepithelium
    • paracrine
    • Received October 30, 2014.
    • Revision received December 21, 2014.
    • Accepted December 23, 2014.
    Renuga Devi Rajaram, Duje Buric, Marian Caikovski, Ayyakkannu Ayyanan, Jacques Rougemont, Jingdong Shan, Seppo J Vainio, Ozden Yalcin‐Ozuysal, Cathrin Brisken
  • Commensal microbiota influence systemic autoimmune responses
    1. Jens T Van Praet1,,
    2. Erin Donovan1,,
    3. Inge Vanassche1,
    4. Michael B Drennan1,
    5. Fien Windels1,
    6. Amélie Dendooven2,
    7. Liesbeth Allais3,
    8. Claude A Cuvelier3,
    9. Fons van de Loo4,
    10. Paula S Norris5,
    11. Andrey A Kruglov6,7,
    12. Sergei A Nedospasov8,
    13. Sylvie Rabot9,10,
    14. Raul Tito11,
    15. Jeroen Raes11,
    16. Valerie Gaboriau‐Routhiau9,12,
    17. Nadine Cerf‐Bensussan12,
    18. Tom Van de Wiele13,
    19. Gérard Eberl14,
    20. Carl F Ware5 and
    21. Dirk Elewaut*,1,15
    1. 1Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
    2. 2Department of Pathology, University Medical Center, Utrecht, the Netherlands
    3. 3Department of Pathology, Ghent University Hospital, Ghent, Belgium
    4. 4Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
    5. 5Infectious and Inflammatory Disease Center, Sanford‐Burnham Medical Research Institute, La Jolla, CA, USA
    6. 6German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany
    7. 7Belozersky Institute of Physico‐Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia
    8. 8Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Lomonosov Moscow State University, Moscow, Russia
    9. 9INRA, UMR1319 Micalis, Jouy‐en‐Josas, France
    10. 10AgroParisTech Micalis, Jouy‐en‐Josas, France
    11. 11Bioinformatics and (eco‐)systems Biology Laboratory, Department of Microbiology and Immunology, Rega Institute VIB Center for the Biology of Disease, KU Leuven, Belgium
    12. 12INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes‐Sorbonne Paris Cité and Institut Imagine, Paris, France
    13. 13Laboratory of Microbial Ecology and Technology, Ghent University, Ghent, Belgium
    14. 14Lymphoid Tissue Development Group, Institut Pasteur, Paris, France
    15. 15VIB Inflammation Research Center Ghent University, Ghent, Belgium
    1. *Corresponding author. Tel: +329 332 2240; E‐mail: Dirk.Elewaut{at}ugent.be
    1. These authors contributed equally to this work

    Neonatal colonization of the intestine by segmented filamentous bacteria affects systemic autoimmune responses against nuclear antigens in adult life.

    Synopsis

    Antinuclear antibodies (ANA) are features of generalized autoimmune diseases. Here, we show that induction of ANA spontaneously occurs in mice lacking gut‐associated lymphoid tissues. This was caused by colonization of the intestine by segmented filamentous bacteria, which are potent inducers of Th17 responses. Microbiota and IL‐17R‐dependent mechanism of ANA induction embark in the neonatal phase of life, leading to systemic autoimmunity in adult.

    • ANA induction may occur in the absence of all secondary lymphoid organs, particularly gut‐associated lymphoid tissues

    • Spontaneous occurrence of ANA in the absence of lymphotoxin is RORγt and IL‐17R dependent.

    • Neonatal colonization of the intestine by segmented filamentous bacteria in the absence of gut‐associated lymphoid tissues predisposes for ANA induction in adult life

    • antinuclear antibodies
    • commensal microbiota
    • systemic autoimmunity
    • Received September 3, 2014.
    • Revision received November 12, 2014.
    • Accepted December 1, 2014.
    Jens T Van Praet, Erin Donovan, Inge Vanassche, Michael B Drennan, Fien Windels, Amélie Dendooven, Liesbeth Allais, Claude A Cuvelier, Fons van de Loo, Paula S Norris, Andrey A Kruglov, Sergei A Nedospasov, Sylvie Rabot, Raul Tito, Jeroen Raes, Valerie Gaboriau‐Routhiau, Nadine Cerf‐Bensussan, Tom Van de Wiele, Gérard Eberl, Carl F Ware, Dirk Elewaut
  • Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB
    1. Miguel B Coelho1,
    2. Jan Attig2,3,
    3. Nicolás Bellora4,5,6,
    4. Julian König37,
    5. Martina Hallegger1,2,
    6. Melis Kayikci3,
    7. Eduardo Eyras4,5,
    8. Jernej Ule2 and
    9. Christopher WJ Smith*,1
    1. 1Department of Biochemistry, University of Cambridge, Cambridge, UK
    2. 2Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    3. 3MRC‐Laboratory of Molecular Biology, Cambridge, UK
    4. 4Computational Genomics, Universitat Pompeu Fabra, Barcelona, Spain
    5. 5Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain
    6. 6INIBIOMA CONICET‐UNComahue, Bariloche, Argentina
    7. 7Institute of Molecular Biology gGmbH (IMB), Mainz, Germany
    1. *Corresponding author. Tel: +44 1223 333655; E‐mail: cwjs1{at}cam.ac.uk

    Matrin3 is a nuclear matrix protein that was recently linked to neurodegeneration. This study finds Matrin3 to be a splicing repressor that modulates hundreds of alternative splice events, offering possible insight on disease onset.

    Synopsis

    Matrin3 is a nuclear matrix protein that was recently linked to neurodegeneration. This study finds Matrin3 to be a splicing repressor that modulates hundreds of alternative splice events, offering possible insight on disease onset.

    • Nuclear matrix protein Matrin3 uses a GILGPPP motif to dock onto the RRM2 domain of splice regulator PTB.

    • Transcriptome‐wide profiling shows changes in hundreds of alternative splicing events (ASE) upon Matrin3 knockdown; only a subset of these are also regulated by PTB.

    • Unlike other splicing regulators, Matrin3 binds to extended regions within and around repressed exons.

    • Matrin3 requires its RRMs and the GILGPPP motif to regulate splicing of both PTB‐dependent and PTB‐independent ASEs, suggesting possible crosstalk with other RRM‐containing splice factors.

    • The finding that Matrin3 plays a role in controlling alternative splicing may help understand the etiology of Matrin3‐associated pathologies.

    • alternative splicing
    • Matrin3
    • PTB
    • Received August 19, 2014.
    • Revision received December 12, 2014.
    • Accepted December 15, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Miguel B Coelho, Jan Attig, Nicolás Bellora, Julian König, Martina Hallegger, Melis Kayikci, Eduardo Eyras, Jernej Ule, Christopher WJ Smith
  • Transport through recycling endosomes requires EHD1 recruitment by a phosphatidylserine translocase
    1. Shoken Lee1,,
    2. Yasunori Uchida1,,
    3. Jiao Wang2,
    4. Tatsuyuki Matsudaira1,
    5. Takatoshi Nakagawa3,
    6. Takuma Kishimoto4,
    7. Kojiro Mukai1,4,
    8. Takehiko Inaba4,
    9. Toshihide Kobayashi4,
    10. Robert S Molday2,
    11. Tomohiko Taguchi*,1,5 and
    12. Hiroyuki Arai*,1,5
    1. 1Department of Health Chemistry, Graduate School of Pharmaceutical Sciences University of Tokyo, Tokyo, Japan
    2. 2Departments of Biochemistry and Molecular Biology and Ophthalmology and Visual Sciences, Centre for Macular Research University of British Columbia, Vancouver, BC, Canada
    3. 3Department of Pharmacology, Osaka Medical College, Takatsuki‐city Osaka, Japan
    4. 4Lipid Biology Laboratory, RIKEN, Wako‐shi Saitama, Japan
    5. 5Pathological Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences University of Tokyo, Tokyo, Japan
    1. * Corresponding author. Tel: +81 3 5841 4725; Fax: +81 3 3818 3173; E‐mail: tom_taguchi{at}mol.f.u-tokyo.ac.jp

      Corresponding author. Tel: +81 3 5841 4720; Fax: +81 3 3818 3173; E‐mail: harai{at}mol.f.u-tokyo.ac.jp

    1. These authors contributed equally to this work

    The aminophospholipid translocase ATP8A1 enriches phosphatidylserine at the cytosolic leaflet of recycling endosomes, recruiting fission protein EHD1. Phosphatidylserine translocation is required for cargo sorting and membrane fission, a process perturbed in CAMRQ disease‐associated ATP8A2 mutant cells.

    Synopsis

    The aminophospholipid translocase ATP8A1 enriches phosphatidylserine at the cytosolic leaflet of recycling endosomes, recruiting fission protein EHD1. Phosphatidylserine translocation is required for cargo sorting and membrane fission, a process perturbed in CAMRQ disease‐associated ATP8A2 mutant cells.

    • P4‐ATPase ATP8A1 flips phosphatidylserine (PS) to the cytosolic leaflet of recycling endosomes (REs).

    • PS recruits membrane fission protein EHD1 to REs.

    • The ATP8A1/PS/EHD1 axis regulates membrane traffic from REs.

    • Membrane traffic defects at REs may underlie a neurodegenerative disease associated with ATP8A2 mutations.

    • ATP8A1
    • EHD1
    • phosphatidylserine
    • phospholipid flippase
    • recycling endosomes
    • Received August 4, 2014.
    • Revision received December 16, 2014.
    • Accepted December 17, 2014.

    This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

    Shoken Lee, Yasunori Uchida, Jiao Wang, Tatsuyuki Matsudaira, Takatoshi Nakagawa, Takuma Kishimoto, Kojiro Mukai, Takehiko Inaba, Toshihide Kobayashi, Robert S Molday, Tomohiko Taguchi, Hiroyuki Arai