Biomedical Engineering Reference
In-Depth Information
Heterozygous and transgenic mice show facial malformation including premature fusion of
the cranial suture in twist +/- mice and a short snout and a twisted upper jaw caused by devel-
opmental defect in the first branchial arch.
77,78
Mutations affecting DNA binding, nuclear
localization, or protein stability are all involved in the haplo-insufficiency of Twist.
79-82
Unlike gene mutations disturbing skeletal patterning and certain cranial biogenesis dis-
cussed above, mutations affecting osteoblast or osteoclast differentiation lead to more general-
ized bone defects. Diseases arising from mutations disrupting osteoblast differentiation are best
characterized in cleidocranial dysplasia (CCD), a heritable skeletal disorder characterized by
abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a
variety of other skeletal changes. In both humans and mice, haplo-insufficiency of Cbfa1 is the
cause of CCD.
30,83
Numerous studies identified the majority of mutations are missense muta-
tions in conserved residues within Runt or PST domains, the two domains responsible for
DNA binding or transactivation ability, respectively.
83-88
In humans, MITF mutations cause Waardenburg syndrome type 2A and Tietz syndrome,
autosomal dominant disorders resulting in deafness and hypopigmentation. Mice deficient in
mi locus also show similar symptoms to humans, but these animals also develop osteopetro-
sis.
57
Mutations leading to impairment of its DNA-binding, dimerization, or transactivation
of MITF at the mi locus affect the development of several different cell types, including osteo-
clasts, melanocytes, and mast cells.
89
Conclusions
In the past 5 years, tremendous progress has been made in identifying transcription factors
involved in the specification of cell lineage of the skeletal system. Mice and humans harboring
mutations affecting skeletal development have provided excellent models to understand the
function of these factors. Knowledge gained from the analysis of these genes has allowed us to
establish a genetic cascade of transcription factors involved in controlling the differentiation
and function of chondrocyte, osteoblast, and osteoclast. However, many questions remain to
be answered. We know little about the genes whose expression is controlled by Sox9, Cbfa1,
Pu.1 and c-Fos that allow them to cause progenitor cells to differentiate into chondrocytes,
osteoblasts, and osteoclast, respectively. It also remains to identify the factors that act in concert
with Cbfa1 to regulate osteoblast differentiation. Since strict temporal and tissue-specific con-
trol of gene expression in eukaryotes is often achieved by coordinate assembly of multiple
transcription factors, we can expect that many more key regulators will be identified in the next
5 years.
Acknowledgements
This work was supported by NIH DE11290 to GK and CBBF.FO1.013.1/4 to XY.
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