Abstract
Author SummaryIn the early mouse embryo, Nodal, a member of the TGFbeta superfamily of signalling proteins, promotes the differentiation of extra-embryonic tissues, as well as tissues within the developing embryo itself. Characterising the regulation of Nodal gene expression is essential to understand how Nodal signals in diverse tissue types and at different stages of embryonic development. Four distinct enhancer sequences have been shown to regulate Nodal expression, although none could account for it in the preimplantation epiblast or in embryonic stem cells. We identified a novel enhancer, HBE, responsible for the earliest aspects of Nodal expression. We show that activation of HBE depends on its interaction with a well-known pluripotency factor called Oct4. HBE itself also controls the activation of at least one other Nodal enhancer. Our findings clarify how early Nodal expression is regulated and reveal how pluripotency factors may control the onset of differentiation in embryonic tissues.
Highlights
The gene Nodal encodes a TGFb family member signaling via the Smad2/3-dependent Activin/Nodal pathway
We show that activation of highly bound element’’ (HBE) depends on its interaction with a wellknown pluripotency factor called Oct4
The higher activity of asymmetric enhancer (ASE) is consistent with it being dependent on Activin/Nodal signaling [6,20,34] and the presence of Activin in epiblast stem cell (EpiSC) culture medium. These results indicate that HBE is the predominant Nodal enhancer in embryonic stem cell (ESC) and that it is still active in EpiSCs
Summary
The gene Nodal encodes a TGFb family member signaling via the Smad2/3-dependent Activin/Nodal pathway. Its re-expression in the adult has been associated with tumor progression and its signaling pathway is essential to the maintenance of human embryonic stem cells (ESCs) [3,4,5]. Nodal expression starts in the inner cell mass (ICM) of the E3.5 blastocyst [6,7]. At E4.0, shortly before implantation, Nodal is detected in the two tissues that derive from the ICM: the epiblast, which will give rise to all fetal lineages, and the primitive endoderm (PrE), an extra-embryonic layer [6]. Nodal expression remains detectable in their postimplantation derivatives up to gastrulation stages but exhibits complex dynamics, foreshadowing the establishment of the anterior–posterior axis and the formation of the primitive streak [1]. Its re-expression in the node at E7.5 and in left lateral plate mesoderm at E8.0 contributes to the establishment of left–right asymmetry [1]
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