Ribosomal modifications are associated with mesenchymal fate selection in the neural crest lineage

Neural crest cells contribute to craniofacial formation by differentiating into skeletogenic mesenchyme and neuro-glial lineages. Using Smart-seq2 single-cell transcriptomics, we show that mesenchymal fate commitment correlates specifically with the expression of rRNA-modifying and ribosome assembly factors, rather than structural ribosomal proteins. Notably, EMG1 and NHP2 introduce key post-transcriptional modifications into 18S rRNA, including m¹acp³ψ at U1248, which requires TSR3 for final maturation. Disrupting NHP2 or TSR3 in vitro and in vivo perturbs cranial neural crest differentiation; post-migratory temporal knockout of Polr1a or Polr1c also causes craniofacial malformations. These findings align with cell type-specific m¹acp³ψ levels during neural crest differentiation. Given the neural crest contribution to neuroblastoma, we analyze patient data to find that elevated ribosomal control and rRNA-modifying proteins predict poorer outcomes. Complementary experiments in neuroblastoma cell lines reveal functional roles for TSR3 and WDR74 in mesenchymal-like tumor states. Together, our results link rRNA modifications and ribosome assembly to fate decisions, suggesting ribosomal heterogeneity shapes both normal development and tumor progression.

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Publication Details

Journal
Nature Communications
Published
2026-03-09
DOI
https://doi.org/10.1038/s41467-026-70375-6
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Ribosomal modifications are associated with mesenchymal fate selection in the neural crest lineage

Kristýna Polášková, Lorena Maili, Paul A. Trainor, Peter V. Kharchenko et al.
Nature Communications
RNA modifications and cancer
article

Ribosomal modifications are associated with mesenchymal fate selection in the neural crest lineage

Kristýna Polášková, Lorena Maili, Paul A. Trainor, Peter V. Kharchenko, Yaakov Gershtein, Alek G. Erickson, Luis F. Montaño-Gutierrez, Lukáš Sourada, Christoph Bartenhagen, Igor I. Adameyko, Per Kogner, Irina Poverennaya, Tomáš Zikmund, Susanne Schlisio, Jaroslav Štěrba, Tobias Steinschaden, Vijay Prakash, Aliia Murtazina, Aurore Attina, Theresa C. Vincent, Anne David, Markéta Kaiser, M. Dominik Fischer, Ornella Clara, Rozalina Galimullina, Teng Gao, Maria Arceo, Adna Goralija, Emma R. Anderson, Bettina Semasch, Jozef Kaiser, Andrei S. Chagin, Shiyuan Chen, Lei Li, Jan Skoda
article en

Abstract

Neural crest cells contribute to craniofacial formation by differentiating into skeletogenic mesenchyme and neuro-glial lineages. Using Smart-seq2 single-cell transcriptomics, we show that mesenchymal fate commitment correlates specifically with the expression of rRNA-modifying and ribosome assembly factors, rather than structural ribosomal proteins. Notably, EMG1 and NHP2 introduce key post-transcriptional modifications into 18S rRNA, including m¹acp³ψ at U1248, which requires TSR3 for final maturation. Disrupting NHP2 or TSR3 in vitro and in vivo perturbs cranial neural crest differentiation; post-migratory temporal knockout of Polr1a or Polr1c also causes craniofacial malformations. These findings align with cell type-specific m¹acp³ψ levels during neural crest differentiation. Given the neural crest contribution to neuroblastoma, we analyze patient data to find that elevated ribosomal control and rRNA-modifying proteins predict poorer outcomes. Complementary experiments in neuroblastoma cell lines reveal functional roles for TSR3 and WDR74 in mesenchymal-like tumor states. Together, our results link rRNA modifications and ribosome assembly to fate decisions, suggesting ribosomal heterogeneity shapes both normal development and tumor progression.

Nature CommunicationsVol. 17(1)
Stowers Institute for Medical Research (US), Fleet Science Center (US), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Central European Institute of Technology (CZ), Harvard University (US), Inserm (FR), Stockholm University (SE), University of Cologne (DE), Université de Montpellier (FR), Masaryk University (CZ), Aix-Marseille Université (FR), Karolinska Institutet (SE), University Hospital Brno (CZ), University of Kansas Medical Center (US), St. Anne's University Hospital Brno (CZ), University Hospital Cologne (DE), Altos Labs, New York University (US), Brno University of Technology (CZ), Medical University of Vienna (AT), University of Gothenburg (SE)
Alex's Lemonade Stand Foundation for Childhood Cancer, Stowers Institute for Medical Research, American Association for Anatomy, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Ministerstvo Školství, Mládeže a Tělovýchovy, Austrian Science Fund, Universität Wien, Ministerstvo Zdravotnictví Ceské Republiky, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Medizinische Universität Wien, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
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RNA modifications and cancer
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