| dc.description.abstract | Craniofacial anomalies account for approximately one-third of all birth defects. Two examples of syndromes associated with craniofacial malformations are Treacher Collins syndrome and Acrofacial Dysostosis, Cincinnati type which have phenotypic overlap including deformities of the eyes, ears, and facial bones. Mutations in TCOF1, POLR1C or POLR1D may cause Treacher Collins syndrome while mutations in POLR1A may cause Acrofacial Dysostosis, Cincinnati type. TCOF1 encodes the nucleolar phosphoprotein Treacle, which functions in rRNA transcription and modification. Previous studies demonstrated that Tcof1 mutations in mice result in reduced ribosome biogenesis and increased neuroepithelial apoptosis. This diminishes the neural crest cell (NCC) progenitor population which contribute to the development of the cranial skeleton. In contrast, apart from being subunits of RNA Polymerases (RNAP) I and/or III, nothing is known about the function of POLR1A, POLR1C, and POLR1D during embryonic and craniofacial development. I therefore examined zebrafish with mutations in polr1a, polr1c, and polr1d to understand the function of RNAPI during embryogenesis. Remarkably, these genes are dynamically expressed during embryonic development and display enriched expression in craniofacial regions, such as the pharyngeal arches, demonstrating that they may have tissue specific functions. Homozygous mutant polr1a, polr1c, and polr1d zebrafish display reduced cranial cartilage formation due to elevated tp53-dependent cell death of NCC progenitors and a diminished population of cranial NCC. In addition, mutant embryos have altered ribosome biogenesis, as demonstrated by reduced rRNA transcription and polysome profiling, which impact the survival and proliferation of cranial NCC. Taken together, this suggests diminished ribosome biogenesis, nucleolar stress, and Tp53-dependent neuroepithelial apoptosis underlie the loss of NCC needed to generate the normal cranioskeletal elements, consistent with the Tcof1 studies. In support of this mechanism, genetic inhibition of tp53 is one approach for improving the skeletal deficiencies in polr1c and polr1d mutants. These zebrafish models represent the first study of RNAPI during craniofacial development and demonstrate that tissue specific phenotypes can arise from disruptions of global processes like ribosome biogenesis. The polr1a, polr1c, and polr1d zebrafish will be useful for further examining RNAPI function as well as finding potential therapies for the prevention of craniofacial anomalies. | |
