RESEARCH INTERESTS:
Cell Fate Determination:
For most immature cell types, decisions between alternative 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 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 strategies 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 can be used to target transgene expression to these different regions of the eye during embryonic development. These promoters have been used to express 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). Microarray techniques are being exploited to define the overall changes in gene expression that occur during ocular differentiation.

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. We have cloned and begun to characterize the genes required for normal left-right asymmetry and for hair follicle induction. The left-right asymmetry gene 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.

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SELECTED PUBLICATIONS:
1. Xie L, Chen H, Overbeek PA, Reneker LW (2007). Elevated insulin signaling disrupts the growth and differentiation pattern of the mouse lens. Mol. Vis. 13: 397-407.

2. Xiao W, Liu W, Li Z, Liang D, Li L, White LD, Fox DA, Overbeek PA, Chen Q (2006). Gene expression profiling in embryonic mouse lenses. Mol. Vis. 12: 1692-1698.

3. Xie L, Overbeek PA, Reneker LW (2006). Ras signaling is essential for lens cell proliferation and lens growth during development. Dev. Biol. 298: 403-414.

4. Mou C, Jackson B, Schneider P, Overbeek PA, Headon DJ (2006). Generation of the primary hair follicle pattern. Proc. Natl. Acad. Sci. USA 103: 9075-9080.

5. Govindarajan V, Overbeek PA (2006). FGF9 can induce endochondral ossification in cranial mesenchyme. BMC Dev. Biol. 6: 7.

6. Govindarajan V, Harrison WR, Xiao N, Liang D, Overbeek PA (2005). Intracorneal positioning of the lens in Pax6-GAL4/VP16 transgenic mice. Mol. Vis. 11: 876-886.

7. Chen Q, Liang D, Yang T, Leone G, Overbeek PA (2004). Distinct capacities of individual E2Fs to induce cell cycle re-entry in postmitotic lens fiber cells of transgenic mice. Dev. Neurosci. 26: 435-445.

8. Reneker LW, Xie L, Xu L, Govindarajan V, Overbeek PA (2004). Activated Ras induces lens epithelial cell hyperplasia but not premature differentiation. Int. J. Dev. Biol. 48: 879-888.

9. Yang T, Liang D, Koch PJ, Hohl D, Kheradmand F, Overbeek PA (2004). Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. Genes Dev. 18: 2354-2358.

For more publications, see listing on Pub Med.

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CONTACT INFORMATION:
Paul A. Overbeek, Ph.D
Department of Molecular & Cellular Biology
Alkek Building, Room N620.03
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030

Telephone: 713-798-6421
Fax: 713-790-1275
E-mail:

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