Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells

Janel L. Kopp, Briana D. Ormsbee, Michelle Desler, A Angie Rizzino

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

Previous studies have demonstrated that the transcription factor Sox2 is essential during the early stages of development. Furthermore, decreasing the expression of Sox2 severely interferes with the self-renewal and pluripotency of embryonic stem (ES) cells. Other studies have shown that Sox2, in conjunction with the transcription factor Oct-3/4, stimulates its own transcription as well as the expression of a growing list of genes (Sox2:Oct-3/4 target genes) that require the cooperative action of Sox2 and Oct-3/4. Remarkably, recent studies have shown that overexpression of Sox2 decreases expression of its own gene, as well as four other Sox2:Oct-3/4 target genes (Oct-3/4, Nanog, Fgf-4, and Utf1). This finding led to the prediction that overexpression of Sox2 in ES cells would trigger their differentiation. In the current study, we initially engineered mouse ES cells for inducible overexpression of Sox2. Using this model system, we demonstrate that small increases (twofold or less) in Sox2 protein trigger the differentiation of ES cells into cells that exhibit markers for a wide range of differentiated cell types, including neuroectoderm, mesoderm, and trophectoderm but not endoderm. We also demonstrate that elevating the levels of Sox2 quickly downregulates several developmentally regulated genes, including Nanog, and a newly identified Sox2:Oct-3/4 target gene, Lefty1. Together, these data argue that the self-renewal of ES cells requires that Sox2 levels be maintained within narrow limits. Thus, Sox2 appears to function as a molecular rheostat that controls the expression of a critical set of embryonic genes, as well as the self-renewal and differentiation of ES cells.

Original languageEnglish (US)
Pages (from-to)903-911
Number of pages9
JournalSTEM CELLS
Volume26
Issue number4
DOIs
StatePublished - Apr 1 2008

Fingerprint

Embryonic Stem Cells
Octamer Transcription Factor-3
Genes
Neural Plate
Endoderm
Mesoderm
Mouse Embryonic Stem Cells
Transcription Factors
Down-Regulation
Proteins

Keywords

  • Development
  • Embryogenesis
  • Fgf-4
  • Mesoderm
  • Nanog
  • Neuroectoderm
  • Oct-3/4
  • Trophectoderm

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. / Kopp, Janel L.; Ormsbee, Briana D.; Desler, Michelle; Rizzino, A Angie.

In: STEM CELLS, Vol. 26, No. 4, 01.04.2008, p. 903-911.

Research output: Contribution to journalArticle

Kopp, Janel L. ; Ormsbee, Briana D. ; Desler, Michelle ; Rizzino, A Angie. / Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. In: STEM CELLS. 2008 ; Vol. 26, No. 4. pp. 903-911.
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