| Title: |
Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice. |
| Authors: |
Sandovici, Ionel; Fernandez-Twinn, Denise S; Campbell, Niamh; Cooper, Wendy N; Sekita, Yoichi; Zvetkova, Ilona; Ferland-McCollough, David; Prosser, Haydn M; Oyama, Lila M; Pantaleão, Lucas C; Cimadomo, Danilo; Barbosa de Queiroz, Karina; Cheuk, Cecilia SK; Smith, Nicola M; Kay, Richard G; Antrobus, Robin; Hoelle, Katharina; Ma, Marcella KL; Smith, Noel H; Geyer, Stefan H; Reissig, Lukas F; Weninger, Wolfgang J; Siddle, Kenneth; Willis, Anne E; Lam, Brian YH; Bushell, Martin; Ozanne, Susan E; Constância, Miguel |
| Publisher Information: |
Elsevier; Department of Obstetrics and Gynaecology; //doi.org/10.1016/j.celrep.2024.114750 |
| Publication Year: |
2024 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
CP: Developmental biology; GH; IGF1; IGF2; adiposity; fetal growth restriction; genomic imprinting; growth hormone; insulin-like growth factor 1; insulin-like growth factor 2; metabolism; miR-483; microRNAs; mid-gestation lethality; Animals; Insulin-Like Growth Factor II; Insulin-Like Growth Factor I; Mice; Female; Pregnancy; Gene Expression Regulation; Developmental; Transgenic; Humans; Fetal Growth Retardation; Inbred C57BL; RNA; Long Noncoding |
| Description: |
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. ; This work was supported by the Medical Research Council (MR/J001562/1 to M.C.; MRC_MC_UU_12014/4 to M.C. and S.E.O.; MRC_MC_UU_12012/5 to the MRC Metabolic Diseases Unit; MR/M009041/1 – “Enhancing UK Clinical Research” grant supporting the TQ-XS work); the Biotechnology and Biological Sciences Research Council (BBSRC BB/F014279/2 to A.E.W. and M.B.) and the Cancer Research UK (CRUK Institute award A29252 to M.B.); N.C. was funded by the Frank Edward Elmore Fund, the Association of Physicians of Great Britain & Ireland and the Anatomical Society; Y.S. was funded by post-doctoral fellowships from the Uehara Memorial Foundation and the Japan Society for the Promotion of Science; D.C. was funded by the Erasmus placement programme; K.B.Q. was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES, Brazil. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/373109; https://doi.org/10.17863/CAM.111666 |
| DOI: |
10.17863/CAM.111666 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/373109; https://doi.org/10.17863/CAM.111666 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.3B21804 |
| Database: |
BASE |