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,
AP-2g,
AP-2d,
and AP-2e. 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.
Selected Publications
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-2a 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).
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