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Faculty William B. Upholt
Professor of Oral Rehabilitation, Biomaterials and Skeletal
Development, Center for Regenerative Medicine and Skeletal Development
Vice Chair, Graduate Programs Committee
upholt@nso2.uchc.edu
Areas of Interest:
We are interested in the genetic regulation of differentiation and
pattern formation during embryonic development. We focus on skeletal
development in the limb and mandible. In terms of differentiation we
study the process of chondrogenesis as the skeletal patterns in these
two organs are first expressed as cartilage models that subsequently get
replaced by bone. Components of the extracellular matrix, including
growth factors as well as structural macromolecules play important roles
in regulating the onset of chondrogenesis.
The homeobox-containing genes, which encode transcription factors, have
emerged as major candidate genes for regulating pattern during
vertebrate development. We have isolated cDNAs or genes of 9 homeobox or
homeobox-related genes expressed in the limb during the process of
pattern formation. The study of the expression of these genes in the
developing limb shows that they are expressed in temporal and spatial
patterns in normal and mutant limbs consistent with their playing
important roles in pattern formation. Recently we have focused on four
such genes, Msx1, Msx2, Dlx5 , and Dlx6 and are in the process of
carrying out experiments to perturb the expression of these two genes in
order to better understand their roles in pattern formation. These same
four genes are expressed in specific temporal and spatial patterns in
the developing mandible. A current major focus is the use of transgenic
mice to delineate specific regulatory elements in the chicken Msx2, Dlx5
and Dlx 6 promoters which are responsible for distinct domains of
expression of these genes in the developing limb and mandible.
Selected Publications:
Wang, C.K., M. Omi, D. Ferrari, H.C. Cheng, G. Lizarraga, H.J. Chin, W.B.
Upholt, C.N. Dealy, and R.A. Kosher, Function of BMPs in the apical
ectoderm of the developing mouse limb. Dev Biol. 269: 109-22 (2004).
Cheng, H.C., C.K. Wang, and W.B. Upholt, Transcriptional regulation
of Msx2 in the AERs of developing limbs is dependent on multiple closely
spaced regulatory elements. Dev Biol. 270: 513-24 (2004). Pan, Z.Z., Kronenberg, M.S., Huang, D.Y., Sumoy, L., Rogina, B.,
Lichtler, A.C., Upholt, W.B. Msx2 expression in the apical ectoderm
ridge is regulated by an MSX2 and Dlx5 binding site. Biochem Biophys Res
Commun. 290: 955-61 (2002).
Lizarrag, G., Lichtler, A., Upholt, W.B., Kosher, R.A. Studies on the
role of Cux1 in regulation of the onset of joint formation in the
developing limb. Dev Biol. 243: 44-54 (2002).
Mina, M., Wang, Y.H., Ivanisevic, A.M., Upholt, W.B., Rodgers, B.
Region- and stage-specific effects of FGFs and BMPs in chick mandibular
morphogenesis. Dev Dyn. 223: 333-52 (2002).
Wang, Y.H., Rutherford, B., Upholt, W.B., Mina, M. Effects of BMP-7 on
mouse tooth mesenchyme and chick mandibular mesenchyme. Dev Dyn. 216:
320-35 (1999).
Ferrari, D., Lichtler, A.C., Pan, Z.Z., Dealy C.N., Upholt, W.B., and
Kosher R.A., Ectopic expression of Msx-2 in posterior limb bud mesoderm
impairs limb morphogenesis while inducing BMP-4 expression, inhibiting
cell proliferation, and promoting apoptosis. Dev. Biol. 196: 12-24
(1998).
Pan, Z., Lichtler, A.C. and Upholt, W.B. DNase I hypersensitive sites in
the chromatin of the chicken Msx2 gene differ in anterior and posterior
limb mesenchyme, calvarial osteoblasts and embryonic fibroblasts.
Biochem Mol Biol Int. 46: 549-57 (1998).
Wang, Y.H., Upholt, W.B., Sharpe, P.T., Kollar, E.J., and Mina, M.
Odontogenic epithelium induces similar molecular responses in chick and
mouse mandibular mesenchyme. Dev. Dyn. 213: 386-97 (1998).
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