2. Molecular basis of Craniosynostosis
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. There is a clear need to develop
adjunct therapies to minimize the need for repeated invasive
cranial surgery and enable proper skull and brain growth.
The underlying causes of the majority of craniosynostoses
are not known and to develop new therapies we need to know
what they are and how they act on skull growth.
In collaboration with surgeons in the Australian Craniofacial
Unit, we have established a bank of tissues and primary cultured
cells from children undergoing operation for craniosynostosis
to enable study of the processes that lead to premature fusion
of the growth regions of the skull. We have shown that cells
from these regions, known as sutures, are able to mineralize
in culture under controlled conditions, providing an indicator
of their bone-forming ability (figure). By comparing gene
activity in tissue from normal and affected sutures using
gene microarrays we identified over 200 genes that are differentially
active between them. Several genes are predicted to be key
regulators of suture fusion and we are now focussing our studies
on them. We have found where some of them are active in the
suture and will continue this and other functional work in
the coming year, extending our studies to mouse genetic models
of Saethre-Chotzen and Crouzon craniosynostosis that we have
recently established in our laboratory.
Bone-forming potential of cultured cranial suture cells.
Mineralization, an indicator of bone-forming potential, is
represented by the dark staining, granular material produced
by the cells (right panel)
A model of suture fusion: a microCT scan of a mouse skull
showing fusion of the posterior frontal suture (arrows) within
the first two weeks of birth. The suture appears as an open
channel between the bony skull plates at day 5 but has largely
fused by day 10
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