Abstract
The skeleton is an important structural framework for vertebrates thatconsists of bone and cartilage. Generally, the vertebrate skeletal system can
be categorized into the appendicular, trunk and craniofacial skeletons. Each
of these have different cellular origins and form through two distinct
mechanisms: endochondral ossification, in which a cartilaginous template is
first formed and then replaced by bone; or intramembranous ossification, in
which cellular precursors are directly differentiated into bone. Some
skeletal structures, such as the mandible, are unique and form via
combinations of both processes. Skeletal dysplasias can affect both types
ossification. Patients with ciliopathies manifest with multiple defects that
affect most skeletal systems. In addition, two other classes of disease, the
craniosynostosis syndromes and the chondrodysplasias, have several
skeletal phenotypes also seen in ciliopathies, such as short limbs and
craniosynostosis. In this project I focus on a ciliopathic mouse model, Fuzzy,
in which both endochondral and intramembranous bones are affected. Cilia
are cellular organelles that have multiple functions from fluid flow to signal
transduction. They are associated with signalling perturbations in different
pathways such as Hedgehog and Wnt. Specifically, I investigate molecular
mechanisms, which cause micrognathia, mandibular hyperossification and
short long bones. Furthermore, this project aims to compare and contrast
some overlapping phenotypes between ciliopathies, chondrodysplasias and
craniosynostosis syndromes, such as vertebral and sternal defects. Results
obtained indicate that many craniofacial defects in the Fuzzy mutant,
including micrognathia, mandibular hyperossification and craniosynostosis,
can be rescued with genetic reduction of Fgf8. Defects affecting other
skeletal elements are not rescued. These data suggest that loss of Fuzzy
converges on Fgf8 regulation during craniofacial development, but effects
on other skeletal systems are probably due to other signalling perturbations,
notably Hedgehog signalling.
| Date of Award | 2015 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Abigail Tucker (Supervisor) & Karen Liu (Supervisor) |