Craniofrontonasal syndrome (CFNS) is an X-linked neurocristopathy characterized by skeletal and neurological anomalies. CFNS is caused by mutations in EFNB1, which encodes EPHRIN-B1, a transmembrane protein and member of the Eph/ephrin family of signaling molecules. Unlike many X-linked conditions, females heterozygous for loss of EFNB1 are more severely affected than hemizygous males. This unique inheritance pattern is due to mosaicism for EFNB1 expression after random X inactivation in heterozygous females. In Efnb1+/- mice, mosaicism leads to active cell sorting between ephrin-B1 expressing and non-expressing cells, resulting in disrupted ephrin-B1 expression boundaries, but the mechanism by which this cell sorting occurs remains incompletely understood. Moreover, cell sorting has not been demonstrated in a human model for CFNS, and it is therefore unknown whether or not cell sorting contributes significantly to disease pathophysiology. One clinically important manifestation of CFNS is coronal craniosynostosis, or premature fusion of the suture between the frontal and parietal bones of the skull. This phenotype is not observed in the Efnb1+/- mouse model, however, presenting an obstacle to understanding its etiology. A human system is therefore needed to understand cellular mechanisms underlying coronal craniosynostosis in CFNS. Human induced pluripotent stem cells (hiPSCs) hold great potential for the study of human disease, as they allow differentiation of patient-specific cells into disease-relevant cell types, which are often difficut or impossible to obtain directly. hiPSCs have been used to model a wide variety of developmental diseases, but they have not been used to model congenital craniofacial anomalies. We have developed a novel hiPSC model for CFNS to study the underlying cellular and molecular etiologies of the disorder and have demonstrated that hiPSC-derived neuroepithelial cells undergo Eph/ephrin-mediated cell sorting. I propose to use our hiPSC model of CFNS to determine the pathways that contribute to Eph/ephrin-mediated cell sorting as well as to study how cell sorting contributes to craniosynostosis in CFNS.
Mutations in the gene EFNB1 cause craniofrontonasal syndrome (CFNS), an X-linked disease that affects multiple different aspects of craniofacial development. This proposal uses human induced pluripotent stem cells to gain a better understanding of the way in which loss of EFNB1 contributes to craniosynostosis, an important clinical manifestation of CFNS as well as a common birth defect. This will inform our understanding about the underlying causes of craniofacial defects in CFNS and has the potential to lead to the development of novel treatment strategies for CFNS and for craniosynostosis in general.
| Niethamer, Terren K; Bush, Jeffrey O (2018) Getting direction(s): The Eph/ephrin signaling system in cell positioning. Dev Biol : |
| Niethamer, Terren K; Larson, Andrew R; O'Neill, Audrey K et al. (2017) EPHRIN-B1 Mosaicism Drives Cell Segregation in Craniofrontonasal Syndrome hiPSC-Derived Neuroepithelial Cells. Stem Cell Reports 8:529-537 |
