Richard S. Mann
The development of multicellular animals requires that all cells have two types of information: where they are relative to their neighbors (positional information) and what structure they should generate (identity information). We are interested in how positional and identity information are integrated during animal development and use the fruit fly, Drosophila melanogaster, as a model system. In recent years, our work has focused on the homeotic selector (HOX) genes which link these two types of information: their large cis regulatory regions interpret positional information and their protein products control cellular identities by regulating the transcription of downstream target genes. The HOX genes have been structurally and functionally conserved throughout evolution and probably perform analogous functions throughout the animal kingdom. We are interested in the following aspects by which HOX proteins control cellular identities: (1) how the HOX proteins select the correct target genes in vivo, (2) post-translational mechanisms controlling HOX function, and (3) the identification of HOX target genes that contribute to segmental differences in the fly.
Although HOX proteins, which all contain a homeodomain, bind to DNA in a sequence-specific manner, their DNA binding specificities usually overlap. For example, the HOX proteins Antennapedia (ANTP) and Ultrabithorax (UBX) have indistinguishable DNA binding specificities in vitro yet generate very different identities in vivo. We have found that HOX specificity is controlled, at least in part, by cofactors that cooperatively bind with HOX proteins to DNA. One of these cofactors is the homeodomain protein encoded by the gene extradenticle (exd). We are biochemically characterizing the EXD-HOX heterodimer and determining the relevance of these heterodimers to HOX specificity in vivo. In addition, we are characterizing the HOX-independent functions of extradenticle during development.
Interestingly, the activity of Extradenticle protein (EXD) is post-translationally controlled. We have found that, throughout development, the nuclear vesus cytoplasmic localization of EXD is regulated. In at least one tissue, the embryonic midgut, EXD's nuclear import is triggered by decapentaplegic (DPP) and wingless (WG), two secreted signaling molecules of the TGB-beta and WNT families, respectively. Because EXD is required for HOX specificity, these findings suggest a mechanism whereby the activity of the HOX proteins can be regulated. Based on these observations, a focus of the lab is to dissect the EXD nuclear localization pathway in the midgut as well as in other places in development.