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

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Ribosomopathies result from altered ribosome component expression, causing tissue-specific phenotypes.
• The mechanisms underlying tissue selectivity in ribosome mutations remain unclear.

Purpose of the Study:

• To investigate the molecular basis for tissue-specific phenotypes in ribosomopathies.
• To elucidate the role of p53 and translational regulation in ribosome-related developmental defects.

Main Methods:

• Utilized mouse genetics to create ribosomal protein (RP) haploinsufficient models.
• Employed in vivo ribosome profiling to analyze translational changes.
• Assessed the impact of p53 and protein synthesis modulation on phenotypes.

Main Results:

• RP haploinsufficiency in mouse embryos caused limb-patterning defects.
• Selective translational changes in limb development transcripts were observed.
• Loss of p53 or augmented protein synthesis rescued these limb phenotypes.
• p53 was identified as a regulator of protein synthesis, partly via transcriptional activation of 4E-BP1.
• 4E-BP1 mediated p53-dependent translatome alterations.

Conclusions:

• p53 acts as a master regulator of protein synthesis, influencing gene expression specificity.
• An integrative model explains how ribosome defects lead to specific in vivo tissue phenotypes in ribosomopathies.
• 4E-BP1 is a key mediator linking p53 function to selective translational control in ribosomopathies.