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Role of transcription factors in development and diseases
We are interested in understanding the role of transcription factors in gene regulation, development and
diseases. Our research has been concentrated in the following three areas:
- BETA2/NeuroD in pancreatic islet and neuronal development
The insulin gene is regulated in a tissue and developmental-specific manner. In our laboratory, we have isolated a tissue-specific
transcription factor BETA2 that can regulate its transcription. Its role in insulin gene activity and islet cell fate determination are
carried out by gene knockout experiment. Results indicate that BETA2 is essential for proper morphogenesis of pancreatic islets and
cell fate determination of several enteroendocrine cells. In addition, we also found that the proper differentiation of several
neuronal cell types such as granule cells of the hippocampus and cerebellum, photoreceptor cells of retina, as well as the ganglions of
the number VIII nerve are compromised. These defects result in behavior abnormalities such as epilepsy, hyperactivity, imbalance and
deafness. Currently, we are analyzing the target genes that are responsible for these defects and modifying mechanism of these defects.
In addition, using Ngn3, a bHLH transcription factor, as a marker and molecular genetic approaches to mark Ngn3 cells, we have isolated
islet progenitor/stem cells. These cells will be characterized for future treatment of diabetes using in vitro produced islets from
these progenitor/stem cells.
- Molecular developmental biology of COUP-Transcription factors
COUP-TFs are orphan members of the steroid/thyroid receptor superfamily. Using a molecular approach in collaboration with Dr.
Sophia Tsai's laboratory, we have found that COUP-TFs are silencers and able to negatively regulate other receptors such as RAR, RXR,
TR, VDR and PPAR activities. These results suggest that they play an important role in cellular development and differentiation. We are
using cellular, molecular and genetic approaches to determine the precise role(s) of these transcription factors in mouse development. Results
indicated that COUP-TFI is important in neurodevelopment, axonal guidance, brain regionalization and bone morphogenesis and COUP-TFII is
important for angiogenesis, heart development, adipogenesis and organogenesis. Currently, we are trying to dissect the underlying mechanism
of these defects.
- Role of nuclear receptor coactivators and corepressors in prostate cancer
It has been shown that androgen and its receptor play an important role in the formation and progression of prostate tumor.
Activation of target genes by androgen receptor, however, requires the participation of coactivators and corepressors. Many cofactors
have been identified to interact with and activate androgen receptor activity. In our laboratory, we are interesting in determining
whether any of these cofactors has a role in prostate tumors. Using in situ hybridization, we have identified SRC-3 to be
over-expressed in 47% of prostate tumor samples. Our goal is to dissect the role of SRC-3 in cell growth and formation of prostate
tumor using transgenic mice as a model.
Selected Publications
Huang HP, Liu M, El-Hodiri HM, Chu K, Jamrich M, Tsai MJ (2000) Regulation of the pancreatic islet-specific gene
BETA2 (neuroD) by neurogenin 3. Molecular and Cellular Biology 20:3292-3307.
Liu M, Pereira FA, Price SD, Chu MJ, Shope C, Himes D, Eatock RA, Brownell WE, Lysakowski A, Tsai MJ (2000) Essential
role of BETA2/NeuroD1 in development of the vestibular and auditory systems. Genes and Development 14:2839-2854.
Zhou C, Tsai SY, Tsai MJ (2001) COUP-TFI: an intrinsic factor for early regionalization of the neocortex.
Genes and Development 15:2054-2059.
Zhou G, Hashimoto Y, Kwak I, Tsai SY, Tsai MJ (2003) Role of the steroid receptor coactivator SRC-3 in cell growth.
Molecular and Cellular Biology 23:7742-7755.
Bramblett DE, Pennesi ME, Wu SM, Tsai MJ (2004) The transcription factor Bhlhb4 is required for rod bipolar
cell maturation. Neuron 43:779-793.
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, 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.
Zhou HJ, Yan J, Luo W, Ayala G, Lin SH, Erdem H, Ittmann M, Tsai SY, Tsai MJ (2005) SRC-3 is required for prostate
cancer cell proliferation and survival. Cancer Research 65:7976-7983.
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.
Cho JH, Tsai MJ (2006) Preferential posterior cerebellum defect in BETA2/NeuroD1 knockout mice is the result of
differential expression of BETA2/NeuroD1 along anterior-posterior axis. Developmental Biology 290:125-138.
Contact Information
- Ming-Jer Tsai, Ph.D.
- Department of Molecular and Cellular Biology
- Baylor College of Medicine
- One Baylor Plaza M734
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-6253
- Fax: (713) 798-8227
- E-mail: mtsai@bcm.tmc.edu
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