Investigating the developmental origins of ciliopathic craniofacial malformations

Student thesis: Doctoral ThesisDoctor of Philosophy


Ciliopathies are a genetically diverse, pleiotropic group of human disorders that exhibit craniofacial skeletal phenotypes. These malformations are caused by perturbations of the structure or function of the primary cilia, a critical signalling organelle. Generally, craniofacial bones affected in ciliopathies are of neural crest cell (NCC) origin. Several ciliopathy models have defects in NCC induction and migration, and this could account for the phenotypes we see in the craniofacial skeleton. In this project, I use mouse and human models of three ciliopathic genes (FUZ, OFDE and BBS10) to characterise the specific contribution of primary cilia in the neural crest to the skeletal phenotypes seen. Observations in the Fuz and Ofdl mutant mice suggest that these proteins are critical in regulating early condensation of the skeletal elements in both the facial and limb mesenchyme. With conditional deletion of Ofdl  revealing that increased facial condensation stems from not only defective neural crest development, but also from intrinsic defects in skeletal progenitors. In addition, a novel missense variant of FUZ (RCFaP) has been discovered using whole genome sequencing in a pair of monozygotic twins exhibiting craniosynostosis. Interestingly, it seems that this variant can rescue ciliogenesis in vitro but the functional state of these cilia remains unknown. Finally, patient derived, human induced pluripotent stem cells (hiPSCs) are available to model ciliopathic phenotypes. Fortuitously, differentiation of neural crest cells is well established in hiPSCs and therefore the early neural crest phenotypes of ciliopathies can be modelled. Bardet-Biedl patient cell lines (with predicted loss of function mutations in BBSED) were differentiated and the subsequent cells were analysed for NCC markers and characteristic migration. Interestingly, mutant cells showed reduced commitment to the neural crest cell lineage. Altogether, this work has led to a deeper understanding of the ciliopathic craniofacial phenotype during development and provided evidence that the aetiology of these phenotypes rests at multiple time points.
Date of Award1 Jun 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorKaren Liu (Supervisor) & Agamemnon Grigoriadis (Supervisor)

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