Translational specialization in pluripotency by RBPMS poises future lineage-decisions

Abstract

During embryonic development, translation is proposed to be uniquely specialized at the exit of pluripotency to rapidly reprogram the proteome and enable lineage commitment1-5. Yet, the fundamental role of translational specialization in programming developmental cell-fate decisions, its mediators and their mode-of-action remain elusive2,3. Here, using human embryonic stem cell-based models, we report that mesoderm commitment from pluripotency is controlled by the translational specialization factor RBPMS. RBPMS-driven translational specialization balances the abundance of cell-fate regulators to authorize accurate lineage decisions upon receiving differentiation signals. Consequently, RBPMS loss, without affecting pluripotency, selectively and severely impedes mesoderm specification and subsequent cardiogenesis. Mechanistically, direct binding of RBPMS to 3’UTRs allows selective translation of developmental cell-fate regulators including integral morphogen signaling components specifying mesoderm. RBPMS loss disrupts the canonical composition of translation initiation complexes resulting in the aberrant retention of initiation factors on ribosomal complexes. Our data unveil how emerging lineage choices from pluripotency are controlled by translational specialization via ribosomal platforms acting as a regulatory nexus for developmental cell fate decisions.