Student thesis: Doctoral ThesisDoctor of Philosophy


Mechanical forces are known to interact with developmental dynamics and post-natal growth processes. The aim of this thesis was to investigate the role of mechanical force in craniofacial development and growth at the molecular, cellular and organ levels by using di erent models. The craniofacial phenotype of mice with a mesenchymal conditional deletion of Pkd2 (Pkd2fl=fl;Wnt1-Cre) was examined using histology, -CT imaging, in situ hybridisation and synchrotron X-ray microtomography. It was shown that Pkd2fl=fl;Wnt1-Cre mice present growth anomalies mostly located in organs subjected to post-natal mechanical stress. The facial features of patients with PKD1 mutations were then studied by 3D photography and dense surface modelling. Speci c facial features in these patients were identi ed and indicated that PKD genes may be involved in human craniofacial growth. In order to further illustrate the interactions between craniofacial growth and external constraints, the craniofacial structure of a series of skulls with intentional deformations was examined by 3D cephalometry, wall thickness analysis and haptic-aided semi-automatic segmentation. Intentional modi cations of the skull vault induced changes in the shape of the orbits and the maxillary sinuses, as well as local changes in vault bone thickness. The e ects of external constraints on soft-tissues were studied through the brain anomalies in four fetuses with extreme skull malformations occurring in FGFR2-related craniosynostoses. Characteristic brain anomalies were described in FGFR2-related craniosynostoses, that were related both to FGFR2 hyperactivation and to abnormal mechanical stress. Mechanotransduction at the cellular level was investigated using a mathematical model for bone deposition in sutures taking into account the data provided by synchrotron X-ray microtomography. Based on these theoretical investigations, it was found that bone deposition in sutures was driven by a mechanics-dependent non-linear instability also giving account for the appearance of sutural interdigitations. Synchrotron microtomography also appeared as a reliable tool for the study of bone microanatomy. Finally, the evolution and development the bucco-hypophyseal canal, an organ that may be involved in mechanosensation, was studied using sonic-pathway related mutant mice, and the maintenance of this canal in development and evolution was related to modulations in sonic-hedgehog pathway related genes. A new technique for the high-resolution imaging of embryonic soft-tissues was also described. Together, these results show that mechanical forces shape craniofacial development and growth at the molecular, cellular and organ levels. The understanding of the processes involved in the recording and the transduction of external forces is of interest in the treatment of congenital and acquired craniofacial disorders.
Date of Award2013
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPaul Sharpe (Supervisor) & Atsushi Ohazama (Supervisor)

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