Download From Fly to Man: The Kindred Genes of Development

From Fly to Man
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ne of the most exciting discoveries to occur in developmental biology in recent years was the
recognition that some of the major genes that determine body shape in lower animals, such as
the fruit fly, play a similar role in mammals, including man. Researchers at NIDCR's
craniofacial research centers at Johns Hopkins University and the University of Southern
California have taken this finding a step further by discovering the first human birth defect to
be caused by a mutation in one of these genes. The birth defect is another form of
craniosynostosis, called Boston type.
The culprit gene, known as MSX2, is a member of the "homeobox" family of genes, a designation that
refers to a characteristic DNA sequence shared by these genes. These master control genes code for
proteins that bind to DNA and direct the activity of still other genes. Homeobox genes determine the
pattern in which embryos develop, directing the formation of specialized body regions - from simple
body segments to complex structures like the head, thorax, abdomen, limbs and digits. MSX2-like genes
were first identified and studied in the fruit fly, and have since been traced back to prehistoric worms
that crawled on earth over 600 million years ago. In the case of Boston type craniosynostosis, a single
misstatement in the MSX2 DNA code was responsible for the early closing of the skull's sutures.
Very recently, a second homeobox gene (MSX1) was
linked to a human craniofacial disorder known as
familial tooth agenesis. People affected with this
disorder are missing their second premolars and third
molars (wisdom teeth). This exciting finding is the
first direct evidence that a homeobox gene controls
dental patterning (tooth number, size, and shape).
The latest chapter in the homeobox gene story
involves Rieger syndrome. This disorder strikes
many parts of the body, producing facial
abnormalities, missing teeth, and serious eye chamber
defects that can lead to glaucoma. Researchers at the
NIDCR-supported craniofacial research center at the
University of Iowa have found the responsible gene,
named RGS, which is a previously unknown human
homeobox gene. A distant relative of RGS is found in the fly, and performs the very basic function of
determining which end of the egg-shaped embryo will become the head.
Earlier work by this research group linked another major group of developmental genes to a human birth
defect that strikes the head and face. Mutations in the PAX-3 gene were identified as the cause of
Waardenburg's syndrome. This disorder affects eye position and produces deafness, differently colored
eyes, and splotches of variously colored hair and skin. PAX-3 is a member of the PAX family of genes,
which share similarities with homeobox genes in that they are developmental genes that code for DNAbinding proteins. The PAX genes are intimately involved in neurological development, including neural
crest cell migration.
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From Fly to Man
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Linking craniofacial defects to key developmental genes, such as the MSX and PAX genes and the
newly discovered RGS gene, is an important step in unraveling the complex genetic interplay that forms
the head, face, and teeth.
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Craniofacial Research -Table of Contents
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