Craniofacial defects and disorders such as cleft lip/palate and Treacher Collins Syndrome frequently decrease the quality of life for affected individuals. Such defects are often caused by problems in the development of cranial neural crest cells (cNCCs), which are embryonic, multipotent, migratory cells that gives rise to bones, connective tissues, and nerves of the head. To develop less invasive treatments for craniofacial defects, it is essential to first identify the disruptions in developmental processes that cause them. cNCCs originate adjacent to the developing brain of the embryo, and then migrate into the facial prominences and branchial arches (BAs). Each subpopulation of cNCCs gives rise to distinct craniofacial structures. cNCCs that migrate into BAI (the anterior-most BA) give rise to the bones of the jaw and some middle ear structures, while those migrating into BAII form other ear structures and the hyoid bone of the neck. A number of genes important for cNCC development have been identified, but axial-specific genes responsible for patterning specific derivatives have not yet been extensively studied. Certain craniofacial defects, including ear malformation, cleft palate, and Eagle?s syndrome (stylohyoid syndrome) are observed when cNCCs that migrate into BAII form structures that are typically derived from BAI cNCCs, leading to improper craniofacial development. Although it is known that Hoxa2 expression transforms the BAI ?ground state? to a BAII cNCC identity, frequently resulting in defects or death, the molecular mechanism of this process has not been elucidated, and very few genes that interact with Hoxa2 to produce this phenotype have been characterized. This study seeks to identify the regulatory relationships between genes that are confer axial-specific identity to cNCCs in BAI and BAII, and to establish the molecular mechanism(s) by which Hoxa2 shapes the derivatives of BAII cNCCs using the mouse as a mammalian model system.
Aim 1 will compare transcriptional profiles and genome-wide chromatin states of cNCCs in BAI and BAII to identify genes and their enhancers that appear to be acting in an axial-specific manner.
Aim 2 will compare BAII cNCCs from wildtype and Hoxa2- null embryos and assay Hoxa2 binding in these cells to determine the extent to which Hoxa2 is responsible for conferring BAII identity to cNCCs. Together, these data will extend our understanding of the underlying developmental processes and etiology of human craniofacial defects and bring the field closer to developing minimally invasive treatments for these conditions.
Craniofacial defects present a number of challenges, with many existing treatments involving expensive and invasive surgical procedures that are particularly stressful for children. Limited understanding of the underlying genetic mechanisms responsible for these defects has restricted progress toward developing novel, less disruptive treatments. This study aims to establish how genes contribute to healthy craniofacial development and how improper gene regulation leads to craniofacial defects, in hopes that this knowledge will eventually facilitate an improvement in treatment and care for affected individuals.
