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

TL;DR

This study shows that ribosomal modifications influence the fate of neural crest cells, affecting craniofacial development and neuroblastoma outcomes.

Contribution

The study identifies specific rRNA modification factors linked to mesenchymal fate in neural crest cells and their role in tumor progression.

Findings

Disruption of rRNA modification factors like NHP2 and TSR3 causes craniofacial malformations.

High levels of ribosomal control proteins in neuroblastoma correlate with poorer patient survival.

TSR3 and WDR74 play functional roles in mesenchymal-like tumor states.

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.

Neural crest cells differentiate into skeletogenic mesenchyme and neuro-glial lineages, thereby contributing to craniofacial formation. Here, single-cell analysis of cranial neural crest shows that specific rRNA modification and ribosome assembly factors contribute to skeletogenic fate. Their disruption causes craniofacial defects, while high levels in neuroblastoma predict poor survival.

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