The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals

Abstract

A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6-IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6(-/-)) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals.

Keywords

ZBED6; IGF2; mouse; muscle growth; metabolic regulation

Published in

Proceedings of the National Academy of Sciences of the United States of America
2018, Volume: 115, number: 9, pages: E2048-E2057 Publisher: NATL ACAD SCIENCES

SLU Authors

• Andersson, Leif

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Texas A&M University
  • Uppsala University

UKÄ Subject classification

Developmental Biology


Publication identifier

DOI: https://doi.org/10.1073/pnas.1719278115

Permanent link to this page (URI)

https://res.slu.se/id/publ/94403