Functional dissection of Drosophila homeodomain transcription factors required for development of the body plan.

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Nearly all animals exhibit some form of segmentation along the anterior-posterior (head to tail) axis.  An example of segmentation of the human body plan is the backbone; where each vertebra represents an individual segment and has a unique structure or morphology.  I am interested in two general questions: first how the normal number of segments is established; and second how a segment is assigned a unique morphology?  To address this rigorously, I use the Drosophila melanogaster (fruit fly) insect model system where the body plan is divided into 14 segmental units (parasegments) along the anterior-posterior axis.  The Drosophila fushi tarazu gene (ftz) encodes a protein FTZ required for determining the number of segments that form during development, and the proboscipedia (pb) and Sex combs reduced (Scr) genes encode proteins PB and SCR that work alone or together to determine the unique identities of 3 segments (maxillary, labial, and first thoracic).  All three proteins share a DNA-binding protein domain called the homeodomain (HD).  HD-containing proteins (HOX) are transcription factors that regulate the transcription of genes, the process that converts information stored in DNA to RNA that can be read by the protein synthesis machinery.  Even though many of the genes regulated by FTZ, PB and SCR have been identified and extensively characterized, there is a lack of knowledge about how these transcription factors work to bring about changes in the pattern of gene transcription.  One key element lacking is a complete description of the functional domain structure of these proteins.  HOX transcription factors have been analyzed for over twenty years, but the mapping of the functional domains has proven difficult.  In recent years, my group and others have found that HD-containing proteins are composed of small peptide motifs that make small contributions to overall activity.  We are interested in a deeper dissection of the roles of these small motifs in development. This knowledge will greatly enhance our understanding of the mechanistic logic behind the segmentation of the insect body plan, and as HOX proteins are also used during the segmentation of the vertebrate (human) body plan, this work has general application to the understanding of the developmental process in general.  Furthermore, as HOX proteins are examples of transcription factors, this work in flies provides important insights of general biological significance and application on mechanisms that control gene expression.  Since, when you look around at the natural world it is the control of gene expression that makes the grass green, blood red and daffodils yellow; the control of gene expression is fundamental to all Biology.