Understanding the mechanisms that govern craniofacial development is very important given that craniofacial malformations account for approximately one third of congenital anomalies. Craniofacial anomalies occur frequently in tissue-specific disorders termed Ribosomopathies. Ribosomopathies result from perturbations in ribosome biogenesis which is a global mechanism required for cell growth, proliferation and survival. One craniofacial birth defect that is also a ribosomopathy is Treacher Collins Syndrome (TCS) which occurs in 1 in 50,000 live births and is characterized by disruptions in the development of neural crest cell (NCC), a population of cells that give rise to most of the craniofacial bone and cartilage. Mutations in TCOF1, POLR1C and POLR1D cause TCS. TCOF1 associates with RNA Polymerase I (Pol I), which transcribes ribosomal RNA (rRNA), a rate-limiting step of ribosome biogenesis. POLR1C and POLR1D are subunits of Pol I and III. Given the global nature and importance of Pol I and III transcription, it is remarkable that perturbation of rRNA transcription results in tissue-specific defects. Therefore, I hypothesize that the tissue-specific defects characteristic of Treacher Collins Syndrome and other ribosomopathies occur due to the dynamic spatiotemporal regulation of Pol I and III subunit activity and rRNA transcription, and spatiotemporal tissue-specific threshold requirements for ribosome biogenesis. More specifically, I propose that NCC require high levels of rRNA transcription and are thus very susceptible to disruptions in rRNA transcription and ribosome biogenesis. This study will address the specific spatiotemporal roles and requirements of Pol I and III subunits and rRNA transcription during embryogenesis. The goal of aim 1 is to investigate the intrinsic requirements for Polr1c in NCC development and its overall function in craniofacial bone and cartilage formation. The purpose of aim 2 is to determine if there is a tissue-specific requirement for rRNA transcription and thus a tissue-specific sensitivity to disruptions in ribosome biogenesis.
Craniofacial birth defects and ribosomopathies account for a compelling number of congenital anomalies and infant mortality and result in significant emotional and economic burden to patients, families and the national health care budgets. Understanding the biological mechanisms that govern craniofacial and embryonic development is essential for developing strategies for the prevention and treatments of congenital disorders. This project investigates the role of ribosomal RNA transcription during craniofacial and embryonic development with the goal of understanding the etiology and pathogenesis of ribosomopathy disorders and their associated craniofacial birth defects.