Coordinate post-transcriptional regulation by microRNAs and RNA binding proteins is critical for early embryonic cell fate decisions

Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation (1). However, little is known about how RBPs and microRNAs coordinate in developmental time to regulate cell fate. Here, we show that coordinate RBP and microRNA control of a single transcript, Profilin 2 (Pfn2), is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3’untranslated region has a binding site for Iron Regulatory Proteins and a nearby binding site for ESC enriched microRNAs (2,3). Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation (4). In contrast, deletion of the iron response element leads to decreased PFN2 and a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. The choreographed microRNA-IRE axis of control on the Pfn2 transcript is essential for two key signal transduction steps during ESC differentiation.