Trevor Williams is an Associate Professor, Department of Molecular, Cellular and Developmental Biology, Yale University.
The AP-2 alpha gene has multiple roles in development of the mammalian skeleton. Dr. Williams has previously generated an AP-2a knockout mice and determined that these mice exhibit midline craniofacial clefting, acrania, and a failure of sternal fusion. In addition, the clavicle is absent from the knockout mice and the radius is also frequently missing. In chimeric mice, composed of wild-type and AP-2a knockout cells, an additional phenotype is observed: duplication of the proximodistal axis of the forelimb. These duplications are manifested as extra digits, or in more extreme cases, extra limbs. Given these intriguing skeletal defects, a major goal of our research effort is to understand how the AP-2a gene controls formation and patterning of the mammalian skeleton.
Forelimb defects in Ap-2a Chimeric Mice.
Dr. Williams is now utilizing AP-2a enhancer sequences to dissect the regulatory hierarchy governing formation of the face and limb. He has previously identified a large region of the AP-2a gene that directs expression of a linked lacZ marker to multiple tissues in which AP-2a is normally expressed. He is now utilizing a similar transient transgenic analysis to delimit the regions responsible for expression in the craniofacial mesenchyme and the limb bud progress zone. The Williams’ group generated and tested multiple constructs and has begun to identify the cis-acting elements regulating AP-2 expression in the frontonasal prominence. Eventually, this analysis will enable Dr. Williams to characterize the trans-acting factors responsible for the critical expression of AP-2 during face formation.
In parallel with these studies, Dr. Williams is also using the AP-2a face and limb enhancer sequences to drive CRE recombinase expression in these two developing structures. They have generated founder lines that direct high levels of CRE recombinase activity to the entire limb bud, with the exception of the AER. Other lines produce high levels of expression in the frontonasal prominence. Together, these reagents will enable their group to manufacture tissue-specific knockouts of multiple genes in the both the face and limb during mouse embryogenesis.
Examples of some of Dr. Williams’ recent 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.