Craniosynostosis
is a common birth defect that affects newborns (1 in 3000 live births)
with manifestations of abnormal skull shape which may result in raised
intracranial pressure, blockage of cerebaral blood flow and airway, impaired
vision and auditory functions, mental retardation and adverse psychological
effects, if not corrected surgically. Both genetic and environmental
factors contribute to craniosynostosis. Recently findings implicate involvement
of transcription factors, such as MSX2 and TWIST, and growth factor receptors,
such as FGFR1 and FGFR2, in several craniosynostotic syndromes. Msx2 is
a member of the msh gene family. It is known to bind DNA through its homeodomain
and transactivate downstream target genes, which are yet to be defined.
The notion that Msx2 gene activity is critical for the normal development
and maintenance of cranial sutures is supported by Msx2 gain-of-function
phenotypes in a human autosomal dominant genetic disorder of skull development--Boston
type craniosynostosis--and in our transgenic mice in which Msx2 is overexpressed
(Figure 1). We find that Msx2 transgenic mice exhibit premature closure
of calvarial sutures as a consequence of excessive bone (Figure 2C). The
precocious closure of the sagittal suture correlates to an increase of
osteogenic progenitors in the osteogenic front. We hypothesize that the
osteogenic front and the suture are critical compartments in controlling
the growth of the membranous bones in the skull. Any perturbation to the
osteogenic front and/or the suture, via either genetic or epigenetic means,
can result in malformation of the skull.
The major goals of current research are to: (1) investigate the effect
on calvarial bone growth and suture morphogenesis as a result of
Msx1 and Msx2 null mutations; (2) study the Bone Morphogenetic Protein
(BMP ) signaling cascade, a regulator of Msx genes, in the normal development
of calvarial sutures; and (3) identify additional regulatory components
involved in the morphogenesis of sutures and the formation of the osteogenic
front.
Figure 1
Figure 2
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