Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K

Cell. 2009 Dec 11;139(6):1096-108. doi: 10.1016/j.cell.2009.11.020.

Abstract

How body size is determined is a long-standing question in biology, yet its regulatory mechanisms remain largely unknown. Here, we find that a conserved microRNA miR-8 and its target, USH, regulate body size in Drosophila. miR-8 null flies are smaller in size and defective in insulin signaling in fat body that is the fly counterpart of liver and adipose tissue. Fat body-specific expression and clonal analyses reveal that miR-8 activates PI3K, thereby promoting fat cell growth cell-autonomously and enhancing organismal growth non-cell-autonomously. Comparative analyses identify USH and its human homolog, FOG2, as the targets of fly miR-8 and human miR-200, respectively. USH/FOG2 inhibits PI3K activity, suppressing cell growth in both flies and humans. FOG2 directly binds to p85alpha, the regulatory subunit of PI3K, and interferes with the formation of a PI3K complex. Our study identifies two novel regulators of insulin signaling, miR-8/miR-200 and USH/FOG2, and suggests their roles in adolescent growth, aging, and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Body Size*
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • MicroRNAs
  • Transcription Factors
  • ZFPM2 protein, human
  • mir-8 microRNA, Drosophila
  • ush protein, Drosophila
  • Phosphatidylinositol 3-Kinases