Epiblast morphogenesis is controlled by selective mRNA decay triggered by LIN28A relocation

Abstract

The embryonic progression from naïve to primed pluripotency is accompanied by the rapid decay of pluripotency-associated mRNAs and a concomitant radical morphogenetic sequence of epiblast polarization, rosette formation and lumenogenesis. The mechanisms triggering and linking these events remain poorly understood. Guided by machine learning and metabolic RNA sequencing, we identified RNA binding proteins (RBPs), especially LIN28A, as primary mRNA decay factors. Using mRNA-RBP interactome capture, we revealed a dramatic increase in LIN28A mRNA binding during the naïve-rosette-primed pluripotency transition, driven by its nucleolar-to-cytoplasmic translocation. Cytoplasmic LIN28A binds to 3′UTRs of pluripotency-associated mRNAs to directly stimulate their decay and drive lumenogenesis. Accordingly, forced nuclear retention of LIN28A impeded lumenogenesis, impaired gastrulation, and caused an unforeseen embryonic multiplication. Selective mRNA decay, driven by nucleo-cytoplasmic RBP translocation, therefore acts as an intrinsic mechanism linking cell identity switches to the control of embryonic growth and morphogenesis.

Molecular Grammar of RNA-binding Protein Interactions in Formation and Function of Ribonucleoprotein Complexes

“…Similarly, phosphorylation of nucleophosmin 1, a nucleolar protein, was shown to be crucial for lowering its partitioning to the nucleolus and additional phosphorylation of distal sites enhanced its retention in the nucleoplasm(Sridharan et al, 2022). Studies such as these show a clear effect of PTMs on RNP formation, but it remains unclear how this contributes to the protein function and the pattern of selective protein binding to RNAs (Vieira-Vieira et al, 2022;Modic et al, 2021).…”