The skeleton is an important structural framework for vertebrates that consists 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.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677230 |
Date | January 2015 |
Creators | Yannakoudakis, Basil |
Contributors | Tucker, Abigail Saffron ; Liu, Karen Jasmine |
Publisher | King's College London (University of London) |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
Source | http://kclpure.kcl.ac.uk/portal/en/theses/skeletal-malformations-in-the-fuzzy-mutant-mouse(7f6cf0f4-1d8e-4cb1-811f-07f781bfc636).html |
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