47 - Ribosome Biogenesis Is Essential for Craniofacial Cartilage and Bone Development

Poster Board Number: 47
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Odd poster #s – first hour
Even poster #s – second hour

Co-authors:

Kristin Watt - Stowers Institute for Medical Research; Paul Trainor - Stowers Institute for Medical Research

Abstract Body : Most of the craniofacial cartilage, bone and connective tissue in the head and face are derived from neural crest cells (NCCs), a migratory cell population specified during early embryogenesis. Previous work in the lab demonstrated that RNA Polymerase I (Pol I)-mediated ribosomal RNA (rRNA) transcription, a rate limiting step in ribosome biogenesis, is elevated in NCCs compared to other tissues. Consequently, NCC-specific disruption of Pol I function in mice leads to increased pre-migratory and migratory NCC death, which results in hypoplastic frontonasal prominences and pharyngeal arches, anomalies characteristic of craniofacial disorders such as Treacher Collins syndrome. Emerging evidence also supports the tight regulation of ribosome biogenesis in differentiating cells, suggesting post-migratory roles during NCC differentiation. To examine the importance of ribosome biogenesis during later stages of craniofacial development, we deleted Polr1a, which makes up the catalytic core of Pol I, with tamoxifen-inducible CreERT2 at E9.5-E13.5, timepoints during which NCCs begin to differentiate into tissues such as cartilage and bone. Polr1a mutants presented with craniofacial anomalies including a smaller head and a cleft palate at E18.5, as well as underlying skeletal changes in the premaxillary, maxillary and palatine bones when gene excision took place at E10.5. To determine the mechanism driving the anatomical abnormalities in these mutants, single-cell RNA sequencing was performed at E12.5. Results showed reduced cartilage and bone progenitor cell populations and pathway analysis supported perturbation of skeletal morphogenesis pathways, indicating perturbed differentiation of NCC-derived mesenchyme. These results support the requirement for ribosome biogenesis in NCCs during their differentiation stage in craniofacial development, when tissue proliferation and growth rely on increased ribosome numbers to meet tissue expansion and differentiation needs. Thus, even though ribosome biogenesis is a global molecular process, it is tissue specifically required during development and in the pathogenesis of birth defects and disease.