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Physiological role of nuclear receptors during development
Our research focuses on two main areas: the first is to examine the physiological role of nuclear orphan receptor
COUP-TFII in mouse development. COUP-TFs are members of the nuclear receptor superfamily. We have previously demonstrated that COUP-TFs,
I and II, function as negative or positive regulators to regulate their target gene expression. COUP-TFI is highly expressed in the CNS and
PNS, and COUP-TFII is highly expressed in the mesenchyme of the developing organs. Although the expression of COUP-TFI and II overlaps,
ablation of either COUP-TF I or II in mice results in lethality, indicating that each has its distinct function and both are vital for
animal survival. COUP-TFI null mutants exhibit defects in axon guidance, myelination, forebrain regionalizaion, bone and inner ear
morphogenesis while COUP-TFII null mutants exhibit defects in angiogenesis and heart development. Currently, we concentrate our effort in
studying the underlying mechanism by which COUP-TFII regulates angiogenesis and heart development using floxed COUP-TFII mice. We are also
examining its role in the development and function of stomach, liver, limb and brain by crossing them to various Cre mice to generate tissue
specific COUP-TFII null mice. Finally, we use chimera analysis and demonstrate that COUP-TFII plays cell autonomous function in limb
outgrowth and umbilical vessel development.
The second area of our research is to study the interaction of oncogenes and hormones in mammary gland tumorigenesis. We generated a
ligand inducible system to express oncogenes in mammary gland and demonstrated ectopic inducible expression of int-2 in mammary gland
results in mammary gland hyperplasia. The induced hyperplasia is reversible, and the extent of hyperplasia depends on the levels and
the length of expression of int-2. Currently, we are using three transgenic models, to induce expression of either int-2, AIB-1 or Cdc25B,
to investigate the interaction of oncogenes and hormones in the transformation of the mammary gland epithelium.
Selected Publications
Pereira FA, Qiu Y, Zhou G, Tsai MJ, Tsai SY (1999) The orphan nuclear receptor COUP-TFII is required
for angiogenesis and heart development. Genes and Development 13:1037-1049.
Zhou C, Qiu Y, Pereira FA, Crair MC, Tsai SY, Tsai MJ (1999) The nuclear orphan receptor COUP-TFI is required for differentiation of
subplate neurons and guidance of thalamocortical axons. Neuron 24:847-859.
Zhou C, Tsai SY, Tsai MJ (2001) COUP-TFI: an intrinsic factor for early regionalization of the neocortex. Genes
and Development 15:2054-2059.
Chua SS, Ma ZQ, Gong L, Lin SH, DeMayo FJ, Tsai SY (2002) Ectopic expression of FGF-3 results in abnormal prostate
and Wolffian duct development. Oncogene 21:1899-1908.
Ngan ES, Ma ZQ, Chua SS, DeMayo FJ, Tsai SY (2002) Inducible expression of FGF-3 in mouse mammary gland. Proceedings
of the National Academy of Sciences U.S.A. 99:11187-11192.
Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ, Tsai SY (2003) Overexpression of Cdc25B, an androgen receptor coactivator, in
prostate cancer. Oncogene 22:734-739.
Lee CT, Li L, Takamoto N, Martin JF, Demayo FJ, Tsai MJ, Tsai SY (2004) The nuclear orphan receptor COUP-TFII is required for
limb and skeletal muscle development. Molecular and Cellular Biology 24:10835-10843.
You LR, Lin FJ, Lee CT, DeMayo FJ, Tsai MJ, Tsai SY (2005) Suppression of Notch signalling by the COUP-TFII
transcription factor regulates vein identity. Nature 435:98-104.
Takamoto N, You LR, Moses K, Chiang C, Zimmer WE, Schwartz RJ, DeMayo FJ, Tsai MJ*, Tsai SY* (2005) COUP-TFII is
essential for radial and anteroposterior patterning of the stomach. Development 132:2179-2189. (*co-corresponding authors)
You LR, Takamoto N, Yu CT, Tanaka T, Kodama T, Demayo FJ, Tsai SY, Tsai MJ (2005) Mouse lacking COUP-TFII as an
animal model of Bochdalek-type congenital diaphragmatic hernia. Proceedings of the National Academy of Sciences U.S.A.
102:16351-16356.
Contact Information
- Sophia Y. Tsai, Ph.D.
- Department of Molecular and Cellular Biology
- Baylor College of Medicine
- One Baylor Plaza M707
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-6251
- Fax: (713) 798-8227
- E-mail: stsai@bcm.tmc.edu
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