Roles of miRNAs in dermal bone development

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DESCRIPTION (provided by applicant): Craniofacial abnormalities are some of the most common structural birth defects that are often associated with developmental disabilities, abnormalities to brain maturation, hearing loss, functional problems related to breathing, eating, and speech. Impaired cranial bone formation and remodeling can contribute to many of these craniofacial abnormalities and pathogenesis of the developing cranial skeletal structures still remains poorly understood. Our preliminary data suggests that, microRNAs (miRNAs) are a new class of abundant gene regulatory molecules, have an important role in cranial intramembranous bone development. This was revealed with a conditional allele of Dicer, an enzyme required for processing of precursors into functional miRNAs, and a Wnt1::Cre construct that is specific to cells originating from the dorsal neural tube, including cranial neural crest cells, which give rise to most of the facial, calvarial and jawbones. The resulting phenotype includes reduced cranial cartilages, completely absent facial bones and extensive ectopic calvarial cartilage suggesting an altered differentiation phenotype. As many of the craniofacial human diseases mentioned above range from mild to very severe, better understanding of both normal and abnormal intramembranous bone development will be will be paramount to the advancement of future diagnoses, treatments and prevention of many craniofacial disorders, diseases and injuries in the human population, including young children. The long-term objective of this project is to understand mechanisms of the cranial bone development and morphogenesis in normal and abnormal conditions. In this proposal, we aim to investigate the biological roles for several previously identified cranial dermal bone-specific candidate miRNAs. The results of this analysis will be used to start a more comprehensive bioinformatics examination to establish how miRNAs control intramembranous osteoblast differentiation. Project Narrative: Each year thousands of children are born with mild to severe craniofacial diseases related to abnormal cranial bone biology. We found that microRNAs, an interesting class of regulatory molecules, are required for normal cranial bone formation. We believe that that learning about functions of these molecules using sophisticated bioinformatics tools will help us understand the mechanism governing normal cranial bone biology and allow us to develop ways to diagnose, prevent and treat various bone-related craniofacial syndromes in the future.