Overexpression of Igf2-derived Mir483 inhibits Igf1 expression and leads to developmental growth restriction and metabolic dysfunction in mice

• Published in: Cell reports (Cambridge) Vol. 43; no. 9; p. 114750
• Main 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 S.K., Smith, Nicola M., Kay, Richard G., Antrobus, Robin, Hoelle, Katharina, Ma, Marcella K.L., Smith, Noel H., Geyer, Stefan H., Reissig, Lukas F., Weninger, Wolfgang J., Siddle, Kenneth, Willis, Anne E., Lam, Brian Y.H., Bushell, Martin, Ozanne, Susan E., Constância, Miguel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2024; Elsevier
• Subjects: adiposity; CP: Developmental biology; fetal growth restriction; genomic imprinting; growth hormone; IGF1; IGF2; insulin-like growth factor 1; insulin-like growth factor 2; metabolism; microRNAs; mid-gestation lethality; miR-483; microRNAs; GH; adiposity; IGF2; genomic imprinting; IGF1; CP: Developmental biology; miR-483; fetal growth restriction; mid-gestation lethality; metabolism; insulin-like growth factor 2; growth hormone; insulin-like growth factor 1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114750

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. [Display omitted] •In the mouse, expression of imprinted Mir483 is dependent on Igf2 transcription•Mir483 is a developmental growth suppressor and Igf1 is a major target gene•Transgenic Mir483 overexpression in utero leads to fetal demise•Post-natal Mir483 overexpression induces growth restriction and excessive adiposity Sandovici et al., using loss- and gain-of-function mouse models, dissect the mechanisms that regulate Mir483 expression and characterize its role in developmental growth and metabolism. They uncover that Mir483 actions repress IGF signaling, in particular Igf1, and function in a manner opposite the growth-promoting host gene Igf2.