Abstract
Dysregulation of ribosome production can lead to a number of developmental disorders called ribosomopathies. Despite the ubiquitous requirement for these cellular machines used in protein synthesis, ribosomopathies manifest in a tissue-specific manner, with many affecting the development of the face. Here we reveal yet another connection between craniofacial development and making ribosomes through the protein Paired Box 9 (PAX9). PAX9 functions as an RNA Polymerase II transcription factor to regulate the expression of proteins required for craniofacial and tooth development in humans. We now expand this function of PAX9 by demonstrating that PAX9 acts outside of the cell nucleolus to regulate the levels of proteins critical for building the small subunit of the ribosome. This function of PAX9 is conserved to the organism Xenopus tropicalis, an established model for human ribosomopathies. Depletion of pax9 leads to craniofacial defects due to abnormalities in neural crest development, a result consistent with that found for depletion of other ribosome biogenesis factors. This work highlights an unexpected layer of how the making of ribosomes is regulated in human cells and during embryonic development.
Highlights
When ribosome biogenesis is genetically disrupted in humans, a number of surprisingly tissue-specific disorders called ribosomopathies arise
We are only beginning to understand the complex process of making human ribosomes, the cellular machines critical for all protein synthesis
In humans, making a ribosome requires hundreds of regulatory factors to ensure proper cellular growth and development. Dysregulation of this process can lead to a number of tissue specific disorders, termed ribosomopathies
Summary
When ribosome biogenesis is genetically disrupted in humans, a number of surprisingly tissue-specific disorders called ribosomopathies arise. Genetic disruption of the TCOF1, POLR1C, or POLR1D genes in the ribosomopathy, Treacher Collins syndrome (TCS, OMIM 154500), results in reduced pre-ribosomal RNA (pre-rRNA) transcription [1,2,3,4]. While these mutations each affect the global process of pre-rRNA transcription, patients have specific defects in craniofacial development. P53 levels are stabilized upon disruptions in ribosome biogenesis when free ribosomal proteins bind to MDM2, the E3 ligase for p53 [9, 10] This stabilization of p53 leads to apoptosis of the developing neural crest cells, resulting in the mandibulofacial dysostosis of TCS
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