Cell Reports (Sep 2024)
Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice
- Ionel Sandovici,
- Denise S. Fernandez-Twinn,
- Niamh Campbell,
- Wendy N. Cooper,
- Yoichi Sekita,
- Ilona Zvetkova,
- David Ferland-McCollough,
- Haydn M. Prosser,
- Lila M. Oyama,
- Lucas C. Pantaleão,
- Danilo Cimadomo,
- Karina Barbosa de Queiroz,
- Cecilia S.K. Cheuk,
- Nicola M. Smith,
- Richard G. Kay,
- Robin Antrobus,
- Katharina Hoelle,
- Marcella K.L. Ma,
- Noel H. Smith,
- Stefan H. Geyer,
- Lukas F. Reissig,
- Wolfgang J. Weninger,
- Kenneth Siddle,
- Anne E. Willis,
- Brian Y.H. Lam,
- Martin Bushell,
- Susan E. Ozanne,
- Miguel Constância
Affiliations
- Ionel Sandovici
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
- Denise S. Fernandez-Twinn
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Niamh Campbell
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
- Wendy N. Cooper
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
- Yoichi Sekita
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
- Ilona Zvetkova
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- David Ferland-McCollough
- Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
- Haydn M. Prosser
- The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK
- Lila M. Oyama
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Departmento de Fisiologia, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
- Lucas C. Pantaleão
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Danilo Cimadomo
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Laboratory of Developmental Biology, Department of Biology and Biotechnology “Lazzaro Spallanzani,” University of Pavia, Pavia, Italy
- Karina Barbosa de Queiroz
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
- Cecilia S.K. Cheuk
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK
- Nicola M. Smith
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Richard G. Kay
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Robin Antrobus
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
- Katharina Hoelle
- Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
- Marcella K.L. Ma
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Noel H. Smith
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Stefan H. Geyer
- Center for Anatomy and Cell Biology, Division of Anatomy, Medical University of Vienna, Vienna, Austria
- Lukas F. Reissig
- Center for Anatomy and Cell Biology, Division of Anatomy, Medical University of Vienna, Vienna, Austria
- Wolfgang J. Weninger
- Center for Anatomy and Cell Biology, Division of Anatomy, Medical University of Vienna, Vienna, Austria
- Kenneth Siddle
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Anne E. Willis
- Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
- Brian Y.H. Lam
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
- Martin Bushell
- Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
- Susan E. Ozanne
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
- Miguel Constância
- Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Obstetrics and Gynaecology and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 9
p. 114750
Abstract
Summary: Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483 expression is dependent on Igf2 transcription and the regulation of the Igf2/H19 imprinting control region. Transgenic Mir483 overexpression in utero causes fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483 post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483 as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19 transcriptional region to limit excessive tissue growth through repression of IGF signaling.
