Biological Sciences

William McGinnis Professor of Biology, UCSD e-mail: wmcginnis@ucsd.edu Lab Homepage: McGinnis Lab

     Many of the body parts of animals begin as segmentally repeated groups of cells that are instructed to develop different shapes by the members of the Hox protein family. One long term objective of research in the McGinnis lab is to understand the molecular interactions that underlie functional specificity in the Hox patterning system. Although the homeodomain-containing Hox transcription factors are at the core of this system, they function as part of large, poorly understood nucleoprotein complexes. It is only in the context of these complexes that the Hox proteins have the ability to shunt cells onto head, thoracic, or abdominal pathways.

    One mechanism that controls whether Hox proteins confer one segemental fate versus another is through their adoption of different transcriptional activation or repression functions. In one instance we have been able to switch an abdominal identity protein to a thoracic identity protein simply by attaching an exogenous transcriptional activation domain. This supports the general model that Hox proteins are promiscuously binding to many chromatin sites, but their adoption of transcriptional activation, repression, or neutral functions on a spectrum of targets underlies their ability to control different morphologies.

    At present, we are pursuing the implications of the above findings. One area of research is to determine how, at a mechanistic level, Hox cofactors normally elicit activation or repression functions from a single protein in the context of DNA regulatory elements. Another area is the study of the activation and repression functions of Hox homologs in different evolutionary lineages to determine how changes in those functions regulate morphological evolution, particularly in the process of macroevolution. Yet other studies involve the isolation and study of Hox realizator genes that generate the cellular changes that sculpt diverse segment morphologies. We are also applying bioinformatic methods and our knowledge of the sequence and transacting factors that regulate Hox enhancers to predict where novel Hox-regulated enhancers reside in Drosophila genomic sequence, and determine Hox enhancer code words. As part of this effort we are studying the evolution of Hox-regulated enhancers in various arthropod lineages.