4.7 Article

Nucleolin loss of function leads to aberrant Fibroblast Growth Factor signaling and craniofacial anomalies

Journal

DEVELOPMENT
Volume 149, Issue 12, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.200349

Keywords

Nucleolin; Ribosomal RNA; Neural crest cells; Craniofacial development; FGF signaling; P53; Zebrafish

Funding

  1. Stowers Institute for Medical Research
  2. American Association for Anatomy Post-Doctoral Fellowship
  3. National Institute of Dental and Craniofacial Research [DE030972]

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This study reveals the tissue-specific functions of Nucleolin in rRNA transcription, post-transcriptional regulation, and embryonic craniofacial development.
Ribosomal RNA (rRNA) transcription and ribosome biogenesis are global processes required for growth and proliferation of all cells, yet perturbation of these processes in vertebrates leads to tissue-specific defects termed ribosomopathies. Mutations in rRNA transcription and processing proteins often lead to craniofacial anomalies; however, the cellular and molecular reasons for these defects are poorly understood. Therefore, we examined the function of the most abundant nucleolar phosphoprotein, Nucleolin (Ncl), in vertebrate development. ncl mutant (ncl(-/-)) zebrafish present with craniofacial anomalies such as mandibulofacial hypoplasia. We observed that ncl(-/-) mutants exhibited decreased rRNA synthesis and p53-dependent apoptosis, consistent with a role in ribosome biogenesis. However, we found that Nucleolin also performs functions not associated with ribosome biogenesis. We discovered that the halflife of fgf8a mRNA was reduced in ncl(-/-) mutants, which perturbed Fgf signaling, resulting in misregulated Sox9a-mediated chondrogenesis and Runx2-mediated osteogenesis. Consistent with this model, exogenous FGF8 treatment significantly rescued the cranioskeletal phenotype in ncl(-/-) zebrafish, suggesting that Nucleolin regulates osteochondroprogenitor differentiation. Our work has therefore uncovered tissue-specific functions for Nucleolin in rRNA transcription and post-transcriptional regulation of growth factor signaling during embryonic craniofacial development.

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