Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase

Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):E1740-8. doi: 10.1073/pnas.1320873111. Epub 2014 Apr 14.


AU-rich element mRNA-binding proteins (AUBPs) are key regulators of development, but how they are controlled and what functional roles they play depends on cellular context. Here, we show that Brf1 (zfp36l1), an AUBP from the Zfp36 protein family, operates downstream of FGF/Erk MAP kinase signaling to regulate pluripotency and cell fate decision making in mouse embryonic stem cells (mESCs). FGF/Erk MAP kinase signaling up-regulates Brf1, which disrupts the expression of core pluripotency-associated genes and attenuates mESC self-renewal without inducing differentiation. These regulatory effects are mediated by rapid and direct destabilization of Brf1 targets, such as Nanog mRNA. Enhancing Brf1 expression does not compromise mESC pluripotency but does preferentially regulate mesendoderm commitment during differentiation, accelerating the expression of primitive streak markers. Together, these studies demonstrate that FGF signals use targeted mRNA degradation by Brf1 to enable rapid posttranscriptional control of gene expression in mESCs.

Keywords: AU-rich element RNA-binding proteins; developmental mechanisms; developmental signaling pathways; gene regulation dynamics; stem cell biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AU Rich Elements / genetics
  • Animals
  • Butyrate Response Factor 1
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / enzymology
  • Endoderm / cytology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation*
  • Half-Life
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • MAP Kinase Signaling System
  • Mesoderm / cytology
  • Mice
  • Nanog Homeobox Protein
  • Nuclear Proteins / metabolism*
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism
  • Protein Binding / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism*
  • Response Elements / genetics
  • Transcription, Genetic*
  • Tristetraprolin / genetics
  • Tristetraprolin / metabolism


  • Butyrate Response Factor 1
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tristetraprolin
  • Zfp36 protein, mouse
  • Zfp36l1 protein, mouse
  • Fibroblast Growth Factors
  • Extracellular Signal-Regulated MAP Kinases

Associated data

  • GEO/GSE40104