The mevalonate pathway regulates primitive streak formation via protein farnesylation

Sci Rep. 2016 Nov 24:6:37697. doi: 10.1038/srep37697.

Abstract

The primitive streak in peri-implantation embryos forms the mesoderm and endoderm and controls cell differentiation. The metabolic cues regulating primitive streak formation remain largely unknown. Here we utilised a mouse embryonic stem (ES) cell differentiation system and a library of well-characterised drugs to identify these metabolic factors. We found that statins, which inhibit the mevalonate metabolic pathway, suppressed primitive streak formation in vitro and in vivo. Using metabolomics and pharmacologic approaches we identified the downstream signalling pathway of mevalonate and revealed that primitive streak formation requires protein farnesylation but not cholesterol synthesis. A tagging-via-substrate approach revealed that nuclear lamin B1 and small G proteins were farnesylated in embryoid bodies and important for primitive streak gene expression. In conclusion, protein farnesylation driven by the mevalonate pathway is a metabolic cue essential for primitive streak formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Down-Regulation / genetics
  • Embryoid Bodies
  • Gene Expression Regulation, Developmental
  • Metabolic Networks and Pathways*
  • Metabolome
  • Metabolomics
  • Mevalonic Acid / metabolism*
  • Mice, Inbred ICR
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Neurogenesis
  • Oligonucleotide Array Sequence Analysis
  • Organogenesis
  • Primitive Streak / embryology*
  • Primitive Streak / metabolism*
  • Protein Prenylation*
  • Zebrafish

Substances

  • Mevalonic Acid