Gradient Morphogens and Body Patterning Mechanisms

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Stephen J. SmallProposal IOS-0744966Gradient morphogens and body patterning mechanisms In the fruit fly Drosophila melanogaster (Dm), the maternal transcription factor Bicoid (Bcd) is distributed in a long range nuclear gradient along the anterior posterior (AP) axis of the early embryo. Mutations in Bcd function cause the complete loss of the head and other anterior structures, and the formation of tail-like structures at both ends of the embryo. At the molecular level, Bcd is a master regulator that specifies anterior development via two major pathways. First, Bcd prevents the translation of Caudal, a protein involved posterior development. Second, Bcd activates transcription of more than twenty target genes, each of which is responsible for part of the network that makes anterior structures. Despite its importance in Dm, Bcd is not found in most insects. However, recent studies suggest that another transcription factor, Orthodentical (Otd), may play the role of master anterior regulator in at least two other insects, which are distantly related to Dm. This is surprising because there is very little amino acid sequence similarity between the Bcd and Otd proteins. In preliminary experiments, a genetic engineering approach was used to replace the maternal Bcd gradient in Dm with a similar gradient of Otd. Surprisingly, maternally provided Otd rescued most of the anterior structures missing in mutants lacking Dm Bcd. Thus, the goal of this research is to understand why proteins of such different structures can provide similar functions in embryonic development. The experiments will define exactly which specific Bcd-dependent activities can be provided by Otd, and then test which parts of the Bcd and Otd proteins are required for turning on the target genes involved in anterior patterning. The results of these experiments will be of great interest to researchers in the fields of developmental biology, molecular evolution, and computational biology, and will have Broader Impacts from a scientific perspective. In terms of educational Broader Impacts, the project will also provide excellent training opportunities for students at the undergraduate and graduate levels, and augment current efforts to attract and train under-represented minority students.