mRNP reassembly triggers selective mRNA decay to drive rapid embryonic morphogenesis

Within a few hours of successful implantation, the mammalian embryo undergoes rapid morphological progression coupled with cell fate commitment. We show that the coordination and correct timing of these events requires reassembly of protein-mRNA interactions led by a two-step activation of LIN28A. Its transcriptional induction is followed by MEK/ERK-dependent phosphorylation of its intrinsically disordered domain (IDR), which promotes LIN28A cytoplasmic translocation and 3'UTR repositioning towards terminal AUU-rich regions bound by PABP. The mRNAs with the most pronounced AUU-multivalency undergo selective decay upon LIN28A phosphorylation, including naïve pluripotency-associated mRNAs. Remarkably, LIN28A ablation or its nuclear retention arrests cell fate by retaining the naïve expression programme, while morphogenesis proceeds to a striking epiblast multiplication with impaired lumenogenesis and gastrulation. This demonstrates the potency of IDR phosphorylation in driving signal-dependent convergence of LIN28A and PABP at specific 3'UTR termini, thus inducing selective mRNA decay to safeguard a coordinated cell fate and morphological transition.