Molecular basis of craniosynostosis
and bone development
One in 2500 children are born with craniosynostosis, a devastating
medical disorder where the bones of the skull fuse prematurely,
resulting in abnormal skull development, visual and neurological
problems and mental impairment. The underlying causes of the
majority of craniosynostoses are not known. To develop adjunctive
therapies in order to minimize the need for repeated invasive
cranial surgery and enable proper skull and brain growth we
need to know what the molecular mechanisms are and how they
act on skull growth. In pursuit of this goal, we are conducting
research on several molecules we discovered in our studies
of children with craniosynostosis.
In our research on glypicans, proteoglycans that regulate
signalling by growth factors, we have found that these proteins
are not only located on the surface of skull bone-forming
cells but that they can also be secreted. This places them
in a unique position to interact with growth factors outside
cells where they can regulate growth factor activity and entry.
In on-going research we are investigating how the manipulation
of these molecules affects the growth and activity of skull
bone-forming cells.
Research on retinol binding protein 4, a protein that binds
and transports vitamin A which is an important vitamin for
bone growth, has identified that it is located in a specific
compartment of skull bone-forming cells. We have also found
that it is produced in several discrete tissue locations in
embryonic bone development which suggests it may have more
specialized functions than previously thought. We have discovered
that expression of another molecule is linked with a crucial
transition zone in developing bones. To enable further studies
of this molecule and its role in bone growth we are making
a specific antibody for it.
Mouse models of craniosynostosis are an important part of
our research. We have completed a gene expression study in
a mouse model of Crouzon-type craniosynostosis and established
colonies of gene knockout models of two glypican genes. In
2011 we plan to study the importance of the glypican genes
in bone development.
A new collaboration was established during the year with
Professor Eric Haan, Dr Sui Yu and Dr Jillian Nicholl of SA
Pathology to determine the causative genes in children presenting
with mental retardation and craniosynostosis. A small region
of one chromosome has been deleted in these children and research
on the genes involved may lead to the identification of a
new gene pathway in skull growth and craniosynostosis.
On-going recruitment of children with craniosynostosis is
essential for our studies. Our collaboration with surgeons
in the Australian Craniofacial Unit, in particular, Senior
Craniofacial Consultant and Associate Professor, Peter Anderson,
continues to be an invaluable relationship.
Prem Dwivedi setting up a suture tissue assay
Jodie Hatfield and Peter Anderson discussing
microscopy data
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