A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies

In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes, such as limb and craniofacial defects as well as bone marrow failure. What accounts for such tissue-selective manifestations and what role translation plays is poorly understood. Combining comprehensive mouse genetics and in vivo​ ribosome profiling, we observe limb patterning phenotypes in ribosomal protein (RP) haploinsufficient embryos and uncover corresponding selective translational changes of transcripts controlling limb development. Surprisingly, either loss of p53, which is activated by RP haploinsufficiency, or augmented protein synthesis rescues these phenotypes. These findings are reconciled by the unexpected identification of p53 as a master regulator of protein synthesis, which specifically induces 4E-BP1 expression. 4E-BP1, a key regulator of gene expression at the translation level, facilitates selective changes in the translatome and thereby explains, at least in part, how RP haploinsufficiency may elicit specificity to gene regulation. These results provide an integrative model to explain how a tissue-specific phenotype may emerge from a mutation in a ribosome component.