Birth Defects of the Craniofacial Skeleton and the Potential for Prevention

Abstract

Craniofacial anomalies account for approximately one‐third of all birth defects, and common anomalies such as cleft palate, craniosynostosis, and mandibulofacial dysostosis can occur in isolation or as part of one of nearly 700 distinct syndromes. Most of the bone, cartilage and connective tissue of the head and face is derived from a stem cell and progenitor cell population called neural crest cells. Congenital craniofacial anomalies are therefore typically associated with defects in neural crest cell development. Understanding the etiology and pathogenesis of craniofacial birth defects is dependent upon knowledge of the mechanisms that govern neural crest cell formation, migration, survival and differentiation. Recently, we discovered that ribosome biogenesis, the process of making ribosomes which are essential for protein translation in all cells, plays an essential role in neural crest cell proliferation and survival during craniofacial development. Ribosome biogenesis commences with transcription of rDNA by RNA Polymerases I and III, and this event is considered a rate‐limiting step in ribosome biogenesis. Mutations in genes that encode subunits of RNA Polymerase I, or its associated factors, lead to deficiencies in ribosome biogenesis, which results in neural crest cell apoptosis, and consequently congenital craniofacial disorders such as Treacher Collins syndrome, and Acrofacial Dysostosis ‐ Cincinnati type. Inhibition of neural crest cell death is capable of ameliorating and in some cases completely preventing craniofacial malformations in mouse and zebrafish models of these syndromes. Through investigating fundamental mechanisms that regulate neural crest cell biology, our work is facilitating the development of therapeutic approaches to prevent the pathogenesis of congenital craniofacial birth defects.Support or Funding InformationStowers Institute for Medical ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.