Open AccessActivin/Nodal Signaling Controls Divergent Transcriptional Networks in Human Embryonic Stem Cells and in Endoderm Progenitors
Author(s) -
Brown Stephanie,
Teo Adrian,
Pauklin Siim,
Hannan Nicholas,
Cho Candy H.H.,
Lim Bing,
Vardy Leah,
Dunn N. Ray,
Trotter Matthew,
Pedersen Roger,
Vallier Ludovic
Publication year - 2011
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.666
Subject(s) - nodal signaling , biology , nodal , endoderm , homeobox protein nanog , nanog homeobox protein , embryonic stem cell , microbiology and biotechnology , activin type 2 receptors , cellular differentiation , rex1 , stem cell , progenitor cell , induced pluripotent stem cell , tgf beta signaling pathway , genetics , transforming growth factor , gene , gastrulation
Activin/Nodal signaling is necessary to maintain pluripotency of human embryonic stem cells (hESCs) and to induce their differentiation toward endoderm. However, the mechanisms by which Activin/Nodal signaling achieves these opposite functions remain unclear. To unravel these mechanisms, we examined the transcriptional network controlled in hESCs by Smad2 and Smad3, which represent the direct effectors of Activin/Nodal signaling. These analyses reveal that Smad2/3 participate in the control of the core transcriptional network characterizing pluripotency, which includes Oct‐4 , Nanog , FoxD3 , Dppa4 , Tert , Myc , and UTF1 . In addition, similar experiments performed on endoderm cells confirm that a broad part of the transcriptional network directing differentiation is downstream of Smad2/3. Therefore, Activin/Nodal signaling appears to control divergent transcriptional networks in hESCs and in endoderm. Importantly, we observed an overlap between the transcriptional network downstream of Nanog and Smad2/3 in hESCs; whereas, functional studies showed that both factors cooperate to control the expression of pluripotency genes. Therefore, the effect of Activin/Nodal signaling on pluripotency and differentiation could be dictated by tissue specific Smad2/3 partners such as Nanog, explaining the mechanisms by which signaling pathways can orchestrate divergent cell fate decisions. S TEM C ELLS 2011;29:1176–1185