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

Area of Science:

• Developmental Biology
• Molecular Biology
• Cancer Research

Background:

• Neural crest cells are vital for craniofacial development, differentiating into various cell types.
• Ribosome biogenesis and function are essential for cellular processes, but their specific roles in cell fate decisions are not fully understood.

Purpose of the Study:

• To investigate the role of ribosome-modifying factors in neural crest cell differentiation.
• To explore the link between ribosomal heterogeneity, craniofacial development, and neuroblastoma progression.

Main Methods:

• Single-cell transcriptomics (Smart-seq2) to analyze gene expression in neural crest cells.
• In vitro and in vivo experiments to disrupt key rRNA-modifying genes (NHP2, TSR3, Polr1a, Polr1c).
• Analysis of neuroblastoma patient data and cell line experiments.

Main Results:

• Mesenchymal fate commitment in neural crest cells correlates with rRNA-modifying and ribosome assembly factors, not structural ribosomal proteins.
• Disruption of NHP2 or TSR3 impairs cranial neural crest differentiation; Polr1a/Polr1c knockout leads to craniofacial malformations.
• Elevated ribosomal control proteins in neuroblastoma patients correlate with poorer outcomes, with TSR3 and WDR74 playing roles in mesenchymal-like tumor states.

Conclusions:

• Ribosome assembly and rRNA modifications are critical regulators of neural crest cell fate decisions during development.
• Ribosomal heterogeneity influences both normal craniofacial development and the progression of neuroblastoma.
• Targeting ribosomal pathways may offer therapeutic strategies for neuroblastoma.