Ribosomal modifications are associated with mesenchymal fate selection in the neural crest lineage.
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Poverennaya Irina, Murtazina Aliia, Li Lei, Maili Lorena, Sourada Lukas, Montano-Gutierrez Luis Fernando, Galimullina Rozalina, Steinschaden Tobias, Kaiser Marketa, Zikmund Tomas, Goralija Adna, Gao Teng, Attina Aurore, Clara Ornella, Bartenhagen Christoph, Erickson Alek G, Gershtein Yaakov, Chen Shiyuan, Polaskova Kristyna, Sterba Jaroslav, Semsch Bettina, Andersson Emma R, Prakash Varsha, Vincent Theresa, Arceo Maria, Kogner Per, Schlisio Susanne, Kharchenko Peter V, David Alexandre, Kaiser Jozef, Fischer Matthias, Skoda Jan, Trainor Paul A, Chagin Andrei S, Adameyko Igor
Аннотация
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.