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-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.
Feng, W., and T. Williams (2003) Cloning and characterization of the mouse AP-2
e gene: a novel family member expressed in the developing
olfactory bulb. Mol. Cell. Neurosci. 24, 460-475.
Nelson, D. and T. Williams. (2004). Frontonasal process-specific disruption of AP-2
a results in postnatal midfacial hypoplasia, vascular anomalies,
and nasal cavity defects. Dev. Biol. 267, 72-92.
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.
Brewer, S. and T. Williams. (2004). Loss of AP-2a impacts
multiple aspects of ventral body wall development and closure. Dev. Biol. 267, 399-417.
Brewer, S. and T. Williams. (Review). (2004). Finally, a sense of closure? Animal models
of human ventral body wall defects . Bioessays, 26, 1307-21.
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