Paired Box 9 (PAX9), the RNA polymerase II transcription factor, regulates human ribosome biogenesis and craniofacial development.

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 organismXenopus tropicalis, an established model for human ribosomopathies. Depletion ofpax9leads 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. Author summary 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. Here, we have discovered a new role for the protein Paired Box 9 (PAX9) in making human ribosomes. While PAX9 has traditionally been known to play a role in regulating the levels of proteins required for craniofacial and tooth development in humans, we expand this function of PAX9 by showing that PAX9 acts outside of the cell nucleolus to regulate the levels of proteins critical for building the small subunit of the ribosome. In addition, we show that this function is conserved to the model organism,Xenopus tropicalis. This link between PAX9's role in craniofacial development and in ribosome biogenesis may lead to new insights into the pathogenesis of thesePAX9mutations in humans.