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). |
