The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Ionel Sandovici; Denise S. Fernandez‐Twinn; Niamh Campbell; Wendy N. Cooper; Yoichi Sekita; Ilona Zvetkova; David Ferland-McCollough; Haydn M. Prosser; Lila M. Oyama; Danilo Cimadomo; Karina Barbosa de Queiroz; Cecilia S. K. Cheuk; Nicola M. Smith; Richard G. Kay; Katharina Hoelle; Noel H. Smith; Stefan H. Geyer; Lukas F. Reissig; Wolfgang J. Weninger; Kenneth Siddle; Anne E. Willis; Martin Bushell; Susan Elizabeth Ozanne; Miguel Constância

doi:10.1101/2022.09.09.507324

Developmental BiologybioRxivSep 9, 2022

Preprint

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Ionel Sandovici iD, Denise S. Fernandez‐Twinn iD, Niamh Campbell, Wendy N. Cooper iD, Yoichi Sekita iD, Ilona Zvetkova iD, David Ferland-McCollough iD, Haydn M. Prosser iD, Lila M. Oyama iD, Danilo Cimadomo iD, Karina Barbosa de Queiroz iD, Cecilia S. K. Cheuk, Nicola M. Smith iD, Richard G. Kay iD, Katharina Hoelle, Noel H. Smith, Stefan H. Geyer iD, Lukas F. Reissig iD, Wolfgang J. Weninger iD, Kenneth Siddle, Anne E. Willis iD, Martin Bushell iD, Susan Elizabeth Ozanne iD, Miguel Constância iD

Abstract

Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.

PDF DOI