Botas 9723681 The goal of this proposal is to understand the molecular mechanisms by which genes control the development of organs and body parts. The proposed work focuses on Hox genes because of their fundamental role in pattern formation and their extraordinary conservation during evolution. Hox genes are used by animals as diverse as worms and mice to control the sizes and shapes of body parts along the major body axis. These master regulatory genes encode homeodomain proteins that regulate the activity of target genes that are mostly unknown. To investigate how Hox genes control pattern formation requires to define the target genes and regulatory sequences recognized by Hox proteins in the developing embryo. One target of Hox regulation in Drosophila is decapentaplegic (dpp), a gene encoding a member of the TGF-( family of proteins. A small (674 bp) enhancer in dpp was defined that mediates direct positive regulation by the Hox gene Ultrabithorax (Ubx) and direct negative regulation by the Hox gene abdominal-A (abd-A). The objectives of the present proposal are: 1) To understand the molecular basis of posterior prevalence. We will investigate whether differences in intrinsic binding affinities or competition for unknown co-factors underlay posterior prevalence. 2) To identify factors required for dpp homeotic regulation. A concerted series of genetic and molecular experiments will be conducted to identify factors conferring Hox specificity in viva. 3) To understand the mechanisms by which ABD-A activates and represses transcription. ABD-A directly represses transcription from one portion of the dpp674 enhancer, but it is able to activate transcription from another portion. Experiments are designed to distinguish these two possibilities: a) ABD-A is both a repressor and an activator depending on the context of the binding sites. b) ABD-A is a repressor that indirectly activates transcription through intermediary proteins. These studies on the molecular mechanisms of Hox func tion will lead to a better understanding of the genetic control of morphogenesis.
