Mail Stop 8120, RC1-S, Rm L18 11111
12801 E. 17th Ave
Aurora, CO 80045
- PhD, Imperial Cancer Research Fund
- University of California at Berkely
- Craniofacial Biology, School of Dental Medicine
- Cell and Developmental Biology
Other Graduate Program Affiliations:
- Biomedical Sciences Program (BSP)
- Medical Scientist Training Program (MSTP)
- Human Medical Genetics
- Molecular Biology
Honors and Awards:
- Cambridge University Senior Scholar
- Cold Spring Harbor Olney Fellow
- Pew Scholar in the Biomedical Sciences
- Timpte/Brownie Endowed Chair in Craniofacial/Molecular Biology
Transcriptional Control of Development and Cancer
Transcription factors are responsible for coordinating gene expression during cell growth and differentiation. Consequently, the inappropriate expression of these molecules can lead to metabolic diseases, developmental defects, and cancer. Our goal is to learn about these processes in the context of the AP-2 family of transcription factors: AP-2a, AP-2ß, and AP-2g. These genes are key regulators of mouse embryogenesis and have been linked to human birth defects and breast cancer.
We employ both in vitro and in vivo analyses, particularly mouse molecular genetics, to study the regulation and function of the AP-2 proteins in mammalian development and cancer. We have shown that mice lacking the AP-2a gene die at birth and have major defects affecting the head and trunk. The AP-2a gene is required for at least six independent developmental processes - formation of the neural tube, face, eye, body wall, limbs, and cardiovascular system. Recently we have succeeded in knocking out a second member of the AP-2 gene family - AP-2g . We have found that AP-2g knockout mice die prior to gastrulation, soon after implantation in the uterus.
Delving deeper, we have discovered that AP-2g is needed solely in the extraembryonic tissues that give rise to the placenta and may control stem cell populations that are important for establishing maternal-fetal interactions. Since the AP-2 genes control multiple aspects of mammalian development, we have now generated mice containing conditional alleles of both the AP-2a and AP-2g genes. These mice will be employed to address how the AP-2 genes regulate specific developmental processes, such as neural crest cell function, placental formation, and craniofacial patterning.
With respect to human disease, over-expression of the AP-2a and AP-2g transcription factors occurs in many breast cancer biopsies. This is an important observation since the AP-2 proteins can alter the expression of several genes linked with the progression of breast cancer, including ERBB2 and the estrogen receptor. We have now mimicked the human situation by generating transgenic animals that over-express AP-2a in the mouse mammary gland. Analysis of these transgenic animals indicates that the AP-2 proteins can act like tumor suppressors to inhibit cell proliferation. We are now generating mammary gland-specific knockouts of the AP-2 genes to gain further insight into their role into normal breast development and breast cancer.
Zhang, J., S. Hagopian-Donaldson, G. Serbedzija, J. Elsemore, D. Plehn-Dujowich, A.P. McMahon, R.A. Flavell and T. Williams (1996). Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature 381, 238-241.
Nottoli, T., S. Hagopian-Donaldson, J. Zhang, A. Perkins and T. Williams (1998). AP-2-null cells disrupt morphogenesis of the eye, face and limbs in chimeric mice. Proc. Natl. Acad. Sci. U.S.A.95, 13714-13719.
Turner, B.C., et al. (1998). Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways. Cancer Research 58, 5466-5472.
Auman, H. J., T. Nottoli, O. Lakiza, Q. Winger, S. Donaldson, and T. Williams (2002). Transcription factor AP-2g is essential in the extraembryonic lineages for early postimplantation development. Development 119, 2733-2747.
Zhang, J, S. Brewer, J. Huang, and T. Williams (2003). Overexpression of transcription factor AP-2a suppresses mammary gland growth and morphogenesis. Developmental Biology 256, 127-145.
Brewer S., W. Feng . J. Huang, S. Sullivan, and T. Williams. (2004). Wnt1-Cre mediated deletion of AP-2a a causes multiple neural crest related defects. Dev. Biol. 267, 135-52.
Bassett, E.A., G. F. Pontoriero, W. Feng, T. Marquardt. M. E. Fini, T. Williams and J. A. West-Mays. (2007) Conditional deletion of AP-2a in the developing retina demonstrates non-cell autonomous roles for AP-2a in optic cup development. Mol. Cell. Biol. 27, 7497-7510.
Feng, W., J. Huang, J. Zhang and T. Williams. (2008) Identification and analysis of a conserved Tcfap2a intronic enhancer element required for expression in facial and limb bud mesenchyme. Mol. Cell. Biol. 28, 315-325.
Wang, X., A. Pasolli, T. Williams, and E. Fuchs. (2008) AP-2 factors act in concert with Notch to transcriptionally orchestrate terminal differentiation in skin epidermis. J. Cell. Biol. 183, 37-48.
Feng, W., F. Simoes-de-Souza, T.E. Finger, D. Restrepo, T. Williams. Disorganized olfactory bulb lamination in mice deficient for transcription factor AP-2e. Molecular and Cellular NeuroSciences (in press).