Altered subcellular localization of transcription factor TEAD4 regulates first mammalian cell lineage commitment

Proc Natl Acad Sci U S A. 2012 May 8;109(19):7362-7. doi: 10.1073/pnas.1201595109. Epub 2012 Apr 23.

Abstract

In the preimplantation mouse embryo, TEAD4 is critical to establishing the trophectoderm (TE)-specific transcriptional program and segregating TE from the inner cell mass (ICM). However, TEAD4 is expressed in the TE and the ICM. Thus, differential function of TEAD4 rather than expression itself regulates specification of the first two cell lineages. We used ChIP sequencing to define genomewide TEAD4 target genes and asked how transcription of TEAD4 target genes is specifically maintained in the TE. Our analyses revealed an evolutionarily conserved mechanism, in which lack of nuclear localization of TEAD4 impairs the TE-specific transcriptional program in inner blastomeres, thereby allowing their maturation toward the ICM lineage. Restoration of TEAD4 nuclear localization maintains the TE-specific transcriptional program in the inner blastomeres and prevents segregation of the TE and ICM lineages and blastocyst formation. We propose that altered subcellular localization of TEAD4 in blastomeres dictates first mammalian cell fate specification.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Blastocyst / metabolism
  • Blastocyst Inner Cell Mass / cytology
  • Blastocyst Inner Cell Mass / metabolism
  • Blastomeres / cytology
  • Blastomeres / metabolism
  • Blotting, Western
  • CDX2 Transcription Factor
  • Cattle
  • Cell Lineage*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryonic Stem Cells / metabolism
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation, Developmental
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Macaca mulatta
  • Mice
  • Mice, Transgenic
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • RNA Interference
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • CDX2 Transcription Factor
  • Cdx2 protein, mouse
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Homeodomain Proteins
  • Muscle Proteins
  • Tead4 protein, mouse
  • Transcription Factors
  • Green Fluorescent Proteins

Associated data

  • GEO/GSE37350