Activin/TGF-beta signaling regulates Nanog expression in the epiblast during gastrulation.

Nanog is required for the maintenance of cellular pluripotency during normal development and in cultured embryonic stem cells. A number of signaling pathways have been implicated in regulating Nanog gene expression in vitro. Using the chick model, we provide in vivo evidence for the involvement of the Activin/TGF-beta signaling pathway in regulating Nanog expression in epiblast cells during gastrulation. Nanog expression in primordial germ cells is not regulated by this pathway, indicating that these two cell types employ different mechanisms for maintaining pluripotency in early development. Furthermore, our data suggest that the bHLH factor E2A plays a role in negatively regulating Nanog expression in vivo. Overall, our data support a direct and positive role of the Smad2/3 mediated TGF-beta signaling pathway in inducing/maintaining Nanog expression.