Orofacial clefts are amongst the most prevalent birth defects occurring in ~1/800 live births worldwide.
Despite progress identifying genetic and environmental risk factors for orofacial clefting, causes of the majority
of isolated cleft cases — particularly clefts of the palate — continue to elude our complete comprehension. A
greater depth of understanding of the molecular underpinnings of orofacial development is therefore essential
for the development of diagnostic, preventative, and therapeutic strategies.
The discovery of vast conserved stretches in the human genome of non-coding regulatory RNAs, such
as microRNAs (miRNAs), has revealed a previously unrecognized layer of genomic information of significance
to human health and disease. Studies proposed in the current application enter this new and challenging
scientific arena to examine the function of miRNAs in orchestrating the complex morphogenetic mechanisms
and gene expression programs underlying formation of the mammalian secondary palate.
These studies, which are a logical extensions of our published comprehensive profile of miRNAs
expressed in the developing facial processes and palate, will investigate the functions of carefully selected
miRNAs in mammalian palatal ontogenesis. Loss/gain of function strategies and in situ hybridization will be
employed to systematically determine the biological functions and spatio-temporal expression patterns during
development of the secondary palate. Results from these studies will elucidate miRNA functionality in specific
aspects of mammalian palatal morphogenesis, growth, and cellular differentiation. The immediate impact of the
proposed research will be delineation of miRNA candidate genes that can be interrogated for human variants
associated with an increased risk of human isolated cleft palate.