Functional Analysis of Rapgef5 in Craniofacial Development and Disease


Craniofacial birth defects are associated with numerous human congenital syndromes and are a leading cause of infant morbidity and mortality. However, despite their impact on health, our understanding of how the head normally develops, and how these processes are disrupted in disease, remains limited. Discovering the genetic and cellular mechanisms that regulate craniofacial development is a critical step towards new treatments, improved patient prognosis, and informed genetic counselling for patients and their families.

We recently discovered that the human congenital heart disease gene, RAPGEF5, is required for both craniofacial and cardiac development. In particular, our data demonstrate that mutations in RAPGEF5 impair critical Wnt signalling activity during development of these regions. In this project, the successful applicant will determine the function and importance of Rapgef5 during formation of the head and identify precisely how impaired Rapgef5 function leads to craniofacial defects. In particular, they will use a combination of advanced gene editing strategies, in vivo and in vitro model systems, state of the art confocal imaging, and a host of molecular biology techniques to fully characterize the Rapgef5 craniofacial phenotype and determine the molecular contribution of Rapgef5 to both normal craniofacial development and disease. Ultimately, the project will generate new molecular understanding of a human disease gene, and elucidate the complex molecular and cellular mechanisms regulating development of the face.


Griffin, J.N., Del Viso, F., Duncan, A.R., Robson, A., Hwang, W., Kulkarni, S., Liu, K.J., Khokha, M.K., (2018). RAPGEF5 Regulates Nuclear Translocation of beta-Catenin. Developmental Cell 44, 248-260 e244.

Deniz, E., Jonas, S., Hooper, M., Griffin, J. N., Choma, M., Khokha, M. (2017). Analysis of Craniocardiac Malformations in Xenopus using OpticalCoherence Tomography. Scientific Reports 7, 42506; doi: 10.1038/srep42506

Kulkarni, S. S., Griffin, J. N., Date, P. P., Liem, K. F., Jr. And Khokha, M. K. (2018). WDR5 Stabilizes Actin Architecture to Promote Multiciliated Cell Formation. Developmental Cell 46, 595-610 e593