RICHARD S. MANN
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.
Noro, B., Culi, J., McKay, DJ, Zhang, W., and Mann RS :(2006)Distinct functions of homeodomain-containing and homeodomain-less isoforms encoded by homothorax.Genes & Development20(12):1636-1650
Crickmore, M. and Mann, RS.:(2006)Hox control of organ size by regulation of morphogen production and mobility.Science313:63-68
Culi, J., Aroca P., Modolell, J. and Mann RS :(2006)jing is required for wing development and to establish the proximo-distal axis of the leg in Drosophila melanogaster.Genetics173:255-266
Ice RJ, Wildonger J, Mann RS, and Hiebert SW.:(2005)Comment on "Nervy links protein kinase A to plexin-mediated semaphorin repulsion".Science309:558
Mann RS and Culi J. :(2005)Developmental biology: morphogens hitch a greasy ride.Nature435:30-33