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Cell fate determination
For most immature cell types, decisions between alternative possible programs of differentiation are made
in response to extracellular signals. Although a variety of extracellular signaling proteins have been identified, the factors
that induce the formation of most adult organs and most terminally differentiated cell types in vertebrates are still unknown.
My laboratory is interested in identifying specific differentiation signals and defining the molecular details of cell fate
determination. Two different strategies are used, both of which make use of transgenic mice. In the first strategy,
differentiation decisions are studied and altered in a model organ, the eye. In the second system, random insertional
mutations are used to identify novel genes that are required for normal embryogenesis.
Within the eye, developmental decisions in the cornea, lens, and retina are all influenced by environmental signals.
Over the years my laboratory has identified and characterized promoters that target transgene expression to these different
regions of the eye during embryonic development. These promoters have been used to drive ectopic expression of extracellular
signaling proteins, such as growth factors, in the eye. Using this strategy, we have discovered that fibroblast growth
factors (FGFs) can specify alternative developmental fates for the different epithelial cells of the eye. We are now working
to identify the signal transduction proteins, transcription factors, and genes that are activated and/or inhibited in vivo in
response to specific FGFs. For example, in the lens, we have shown that FGF receptor stimulation leads to nuclear translocation
of the critical transcription factor Prox1, followed by enhanced expression of both the cell cycle inhibitor p57 (which
inhibits further cellular proliferation), and the transcription factor c-maf (which regulates crystallin gene expression). We
are also using cDNA microarrays to define the overall changes in gene expression that occur during different ocular
differentiation programs.
In addition to the research on eye development, we generate and characterize mice with novel developmental mutations.
To date we have identified mutations that affect left-right asymmetry, sex determination, hair follicle induction, CNS
morphogenesis, craniofacial and inner ear development, skin maturation, growth, fertility, and social behavior, as examples.
The left-right mutation and the hair follicle mutation have been studied in detail. The mutated gene that is required for
normal left-right asymmetry encodes a novel protein termed inversin. The gene for hair follicle induction, termed downless,
encodes a novel member of the TNF receptor family. Current research is focused on identifying the molecular mechanisms by
which inversin and downless regulate specific morphogenetic programs during embryogenesis.
Selected Publications
Headon DJ, Overbeek PA (1999) Involvement of a novel Tnf receptor homologue in hair follicle
induction. Nature Genetics 22:370-374.
Govindarajan V, Overbeek PA (2001) Secreted FGFR3, but not FGFR1, inhibits lens fiber differentiation.
Development 128:1617-1627.
Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, Boettger-Tong HL, Bishop CE, Agoulnik AI
(2001) A transgenic insertion causing cryptorchidism in mice. Genesis 30:26-35.
Zhao S, Overbeek PA (2001) Elevated TGFβ signaling inhibits ocular vascular development. Developmental
Biology 237:45-53.
Zhao S, Hung FC, Colvin JS, White A, Dai W, Lovicu FJ, Ornitz DM, Overbeek PA (2001) Patterning the optic
neuroepithelium by FGF signaling and Ras activation. Development 128:5051-5060.
Chen Q, Ash JD, Branton P, Fromm L, Overbeek PA (2002) Inhibition of crystallin expression and induction
of apoptosis by lens-specific E1A expression in transgenic mice. Oncogene 21:1028-1037.
Hung FC, Zhao S, Chen Q, Overbeek PA (2002) Retinal ablation and altered lens differentiation induced by
ocular overexpression of BMP7. Vision Research 42:427-438.
Chen Q, Dowhan DH, Liang D, Moore DD, Overbeek PA (2002) CREB-binding protein/p300 co-activation of
crystallin gene expression. Journal of Biological Chemistry 277:24081-24089.
Zhao S, Chen Q, Hung FC, Overbeek PA (2002) BMP signaling is required for development of the ciliary
body. Development 129:4435-4442.
Contact Information
- Paul A. Overbeek, Ph.D.
- Department of Molecular and Cellular Biology
- Baylor College of Medicine
- One Baylor Plaza N620.03
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-6421
- Fax: (713) 790-1275
- E-mail: overbeek@bcm.tmc.edu
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