Cell-fate determination by ubiquitin-dependent regulation of translation
Open accessAbstract
Metazoan development depends on the accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation requires changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell-fate determination is less well understood. Here we identify the ubiquitin ligase CUL3 in complex with its vertebrate-specific substrate adaptor KBTBD8 (CUL3(KBTBD8)) as an essential regulator of human and Xenopus tropicalis neural crest specification. CUL3(KBTBD8) monoubiquitylates NOLC1 and its paralogue TCOF1, the mutation of which underlies the neurocristopathy Treacher Collins syndrome. 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 favour of neural crest specification. We conclude that ubiquitin-dependent regulation of translation is an important feature of cell-fate determination.
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EGR1 is implicated in cranial development in animal models, and its promoter has been shown to feature a bivalent state in human embryonic cranial neural crest.
“which is implicated in cranial development (in animal models) (33, 34) and whose promoter has been recently shown to feature a bivalent state in human embryonic cranial NC (23, 35).”
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- Authors
- Werner, A., Iwasaki, S., McGourty, C. A., Medina-Ruiz, S., Teerikorpi, N., Fedrigo, I., Ingolia, N. T., & Rape, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Berkeley (US)
- Venue
- Nature
- Published
- 2015-09
- Volume
- 525
- Issue
- 7570
- Pages
- 523-527
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4602398
- OpenAlex
- W2173122519
- Cited by
- 184
- References
- 36
- Citations by year
- 2026: 4 · 2025: 20 · 2024: 21 · 2023: 13 · 2022: 24 · 2021: 18 · 2020: 18 · 2019: 14 · 2018: 16 · 2017: 21 · 2016: 12 · 2015: 1
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10rr025622-01)
- National Institute of General Medical Sciences (GM 42341, R01GM042341, R01GM083064)
- National Institute of Dental and Craniofacial Research (K99DE025314)
- National Center for Research Resources (S10 RR025622, S10RR029668, S10RR027303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- ubiquitin ligase, CUL3, NOLC1, TCOF1, Treacher Collins syndrome, neural crest specification, cell fate determination, post-transcriptional regulation, translational regulation, ribosome biogenesis, RNA polymerase I, embryonic stem cell differentiation, Xenopus tropicalis, ubiquitination
- MeSH terms
- Animals, Cell Differentiation, Humans, Mandibulofacial Dysostosis, Neural Crest, Nuclear Proteins, Phosphoproteins, Ribosomes, RNA Polymerase I, Protein Biosynthesis, Xenopus, Ubiquitin, Proteomics, Cullin Proteins, Adaptor Proteins, Signal Transducing, Embryonic Stem Cells, Ubiquitination
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