Craniofacial anomalies are common human birth defects that have dramatic impact on the quality of life of the affected individual. To date, the bulk of our understanding of these congenital anomalies has depended on mouse models, which, though invaluable, have limitations in their use in understanding human diseases. Human induced pluripotent stem cells (hiPSCs) provide a promising platform for the study of the consequences of patient-specific mutations in disease-relevant cell types. Craniofrontonasal syndrome (CFNS) is an X-linked disease that causes dramatic craniofacial dysmorphogenesis in patients that are mosaic for mutations in the EFNB1 gene. Our preliminary studies in mouse models, in combination with published work, indicate that ephrin-B1 acts to re-organize craniofacial tissues based on a cellular phenomenon known as cell sorting. Eph/ephrin-mediated cell sorting is common to multiple developmental systems, but the cellular and molecular mechanisms at play are incompletely understood. We have established patient-specific hiPSCs from multiple individuals in a family affected by CFNS and have developed a developmentally relevant human cellular model system for understanding this congenital craniofacial disease. We will determine the basic cellular mechanisms by which cell sorting occurs and determine how Eph/Ephrin-mediated signaling is regulated in CFNS patient-derived cell types.
Human induced pluripotent stem cells (hiPSCs) hold great promise for studying mechanisms of disease, but so far have not been applied to the study of congenital craniofacial disease. We have now established an hiPSC model of craniofrontonasal syndrome (CFNS), an X-linked disease that affects multiple aspects of craniofacial development and is caused by aberrant Eph/ephrin cell sorting. This proposal seeks to utilize this novel hiPSC model to understand basic cellular and regulatory mechanisms underlying CFNS.