CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells

Stem Cell Reports. 2016 Dec 13;7(6):1037-1049. doi: 10.1016/j.stemcr.2016.10.002. Epub 2016 Nov 3.


The transcriptional regulator CITED2 is essential for heart development. Here, we investigated the role of CITED2 in the specification of cardiac cell fate from mouse embryonic stem cells (ESC). The overexpression of CITED2 in undifferentiated ESC was sufficient to promote cardiac cell emergence upon differentiation. Conversely, the depletion of Cited2 at the onset of differentiation resulted in a decline of ESC ability to generate cardiac cells. Moreover, loss of Cited2 expression impairs the expression of early mesoderm markers and cardiogenic transcription factors (Isl1, Gata4, Tbx5). The cardiogenic defects in Cited2-depleted cells were rescued by treatment with recombinant CITED2 protein. We showed that Cited2 expression is enriched in cardiac progenitors either derived from ESC or mouse embryonic hearts. Finally, we demonstrated that CITED2 and ISL1 proteins interact physically and cooperate to promote ESC differentiation toward cardiomyocytes. Collectively, our results show that Cited2 plays a pivotal role in cardiac commitment of ESC.

Keywords: Cited2; Isl1; cardiac progenitor; differentiation; embryonic stem cell; transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Lineage
  • Gene Expression Regulation, Developmental
  • Humans
  • LIM-Homeodomain Proteins / metabolism*
  • Mesoderm / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism*
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism*
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*


  • Cited2 protein, mouse
  • LIM-Homeodomain Proteins
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1