Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice
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.
Authors
- Martin Bushell (ORCID: https://orcid.org/0000-0001-9938-2691)
- Wendy N. Cooper (ORCID: https://orcid.org/0000-0003-3416-9982)
- Marcella Ma (ORCID: https://orcid.org/0000-0002-2228-7466)
- Lila Missae Oyama (ORCID: https://orcid.org/0000-0002-7078-6526)
- Cecilia S.K. Cheuk
- Brian Y.H. Lam (ORCID: https://orcid.org/0000-0002-3638-9025)
- Miguel Constância (ORCID: https://orcid.org/0000-0002-8976-1679)
- Anne E. Willis (ORCID: https://orcid.org/0000-0002-1470-8531)
- Danilo Cimadomo (ORCID: https://orcid.org/0000-0002-5390-9221)
- Ilona Zvetkova (ORCID: https://orcid.org/0000-0003-4356-0086)
- Ionel Sandovici (ORCID: https://orcid.org/0000-0001-5674-4269)
- Denise S. Fernandez‐Twinn (ORCID: https://orcid.org/0000-0003-2610-277X)
- Richard G. Kay (ORCID: https://orcid.org/0000-0002-3827-8687)
- Yoichi Sekita (ORCID: https://orcid.org/0000-0002-6230-8719)
- Susan E. Ozanne (ORCID: https://orcid.org/0000-0001-8753-5144)
- Stefan H. Geyer (ORCID: https://orcid.org/0000-0003-2283-4439)
- Lukas F. Reissig (ORCID: https://orcid.org/0000-0001-5833-8176)
- Kenneth Siddle
- Nicola M. Smith (ORCID: https://orcid.org/0000-0002-5137-1384)
- Niamh Campbell
- Robin Antrobus (ORCID: https://orcid.org/0000-0001-8608-4011)
- Haydn M. Prosser (ORCID: https://orcid.org/0000-0002-9897-2152)
- David Ferland-McCollough (ORCID: https://orcid.org/0000-0002-3284-8765)
- Katharina Hoelle
- Wolfgang J. Weninger (ORCID: https://orcid.org/0000-0003-0575-0073)
- Karina Barbosa de Queiroz
- Lucas C. Pantaleão (ORCID: https://orcid.org/0000-0002-5626-8810)
- Noel H. Smith
Institutions
- University of Leicester (GB)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- National Institute for Health and Care Research (GB)
- Cambridge School (PT)
- Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT)
- Bridge University (SS)
- Wellcome/MRC Institute of Metabolic Science (GB)
- MRC Epidemiology Unit (GB)
- NIHR Cambridge Biomedical Research Centre (GB)
- Medical University of Vienna (AT)
- Medical Research Council (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114750
- Citations
- 8
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 4.58
Funders
- Francis Crick Institute
- Anatomical Society
- Cancer Research UK
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Japan Society for the Promotion of Science