Paul A. Overbeek, Ph.D.
Professor of Molecular and Human Genetics
B.A., Kalamazoo College, 1973
M.S., University of Michigan, 1975
Ph.D., University of Michigan, 1980
M.B.A., University of Chicago, 1982
Postdoc, National Institute of Child Health and Human Development, National Institutes of Health, 1985
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.
- Sharov AA, Mardaryev AN, Sharova TY, Grachtchouk M, Atoyan R, Byers HR, Seykora JT, Overbeek P, Dlugosz A, Botchkarev VA (2009). Bone morphogenetic protein antagonist noggin promotes skin tumorigenesis via stimulation of the Wnt and Shh signaling pathways. Am. J. Pathol. 175(3): 1303-14. PubMed PMID: 19700758
- Zhang Y, Tomann P, Andl T, Gallant NM, Huelsken J, Jerchow B, Birchmeier W, Paus R, Piccolo S, Mikkola ML, Morrisey EE, Overbeek PA, Scheidereit C, Millar SE, Schmidt-Ullrich R (2009). Reciprocal requirements for EDA/EDAR/NF-kappaB and Wnt/beta-catenin signaling pathways in hair follicle induction. Dev. Cell. 17(1): 49-61. PubMed PMID: 19619491
- Heath J, Langton AK, Hammond NL, Overbeek PA, Dixon MJ, Headon DJ (2009). Hair follicles are required for optimal growth during lateral skin expansion. J. Invest. Dermatol. 129(10): 2358-64. PubMed PMID: 19387480
- Davis N, Yoffe C, Raviv S, Antes R, Berger J, Holzmann S, Stoykova A, Overbeek PA, Tamm ER, Ashery-Padan R (2009). Pax6 dosage requirements in iris and ciliary body differentiation. Dev. Biol. 333(1): 132-42. PubMed PMID: 19563798
- Zhang Y, Burgess D, Overbeek PA, Govindarajan V (2008). Dominant inhibition of lens placode formation in mice. Dev. Biol. 323(1): 53-63. PubMed PMID: 18778700
- Plas DT, Dhande OS, Lopez JE, Murali D, Thaller C, Henkemeyer M, Furuta Y, Overbeek P, Crair MC (2008). Bone morphogenetic proteins, eye patterning, and retinocollicular map formation in the mouse. J. Neurosci. 28(28): 7057-67. PubMed PMID: 18614674
- Chen Q, Liang D, Overbeek PA (2008). Overexpression of E2F5/p130, but not E2F5 alone, can inhibit E2F-induced cell cycle entry in transgenic mice. Mol. Vis. 14: 602-14. PubMed PMID: 18385796
- Boswell BA, Overbeek PA, Musil LS (2008). Essential role of BMPs in FGF-induced secondary lens fiber differentiation. Dev. Biol. 324(2): 202-12. PubMed PMID: 18848538
- Zhang Y, Overbeek PA, Govindarajan V (2007). Perinatal ablation of the mouse lens causes multiple anterior chamber defects. Mol. Vis. 13: 2289-300. PubMed PMID: 18199970
Paul A. Overbeek, Ph.D
Department of Molecular & Cellular Biology
Baylor College of Medicine
One Baylor Plaza, MS BCM130
Houston, TX, 77030, U.S.A.