Fetal Deficiency of Lin28 Programs Life-Long Aberrations in Growth and Glucose Metabolism

Authors

  • Gen Shinoda,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Ng Shyh-Chang,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
    3. Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, Massachusetts, USA
    4. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
    5. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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  • T. Yvanka de Soysa,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Hao Zhu,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Marc T. Seligson,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Samar P. Shah,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Nora Abo-Sido,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Akiko Yabuuchi,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • John P. Hagan,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
    3. Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, Massachusetts, USA
    4. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, Ohio, USA
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  • Richard I. Gregory,

    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
    3. Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, Massachusetts, USA
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  • John M. Asara,

    1. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
    2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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  • Lewis C. Cantley,

    1. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
    2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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  • Eric G. Moss,

    1. Department of Molecular Biology, The University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
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  • George Q. Daley

    Corresponding author
    1. Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA
    2. Manton Center for Orphan Disease Research, Boston, Massachusetts, USA
    3. Harvard Stem Cell Institute, Boston, Massachusetts, USA
    4. Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, Massachusetts, USA
    5. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA
    6. Howard Hughes Medical Institute, Boston, Massachusetts, USA
    • Children's Hospital Boston, One Blackfan Circle, Karp Building, Seventh Floor, Boston, Massachusetts 02115, USA===

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    • Telephone: 617-919-2013; Fax: 617-730-0222


  • Author contributions: G.S.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; N.S.C. and J.M.A.: collection and/or assembly of data and data analysis and interpretation; T.Y.S., H.Z., M.T.S., S.P.S., and N.A.S.: collection and/or assembly of data; A.Y., J.P.H., R.I.G., and E.G.M.: provision of study materials; L.C.C.: data analysis and interpretation; G.Q.D.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

Abstract

LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of Lin28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of Lin28a and Lin28b deficiency in knockout (KO) mice. Lin28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deletion at specific developmental stages revealed that fetal but neither neonatal nor adult deficiency resulted in growth defects and aberrations in glucose metabolism. Tissue-specific KO mice implicated skeletal muscle-deficiency in the abnormal programming of adult growth and metabolism. The effects of Lin28b KO could be rescued by Tsc1 haplo-insufficiency in skeletal muscles. Our data implicate fetal expression of Lin28a/b in the regulation of life-long effects on metabolism and growth, and demonstrate that fetal Lin28b acts at least in part via mTORC1 signaling. STEM Cells 2013;31:1563–1573

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