Cell fate determination by ubiquitin-dependent regulation of translation

Metazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates (1). Differentiation requires changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Here, we have identified the vertebrate-specific ubiquitin ligase CUL3(KBTBD8) as an essential regulator of neural crest specification. CUL3(KBTBD8) monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the neurocristopathy Treacher Collins Syndrome (2,3). Ubiquitylation drives formation of a TCOF1-NOLC1 platform that connects RNA polymerase I with ribosome modification enzymes and remodels the translational program of differentiating cells in favor of neural crest specification. We conclude that ubiquitin-dependent regulation of translation is an important feature of cell fate determination.