The problem of how genes dictate development of higher organisms is perhaps the most important and appealing in modern biology. The proposed research is directed toward the solution of that problem. Drosophila melanogaster is the preferred organism for attempting this solution, first because its small genome is, among higher eukaryotes, the best defined, second because the genes that select developmental pathways are best defined in Drosophila, and finally because the recent development of a system for germ line transformation by cloned DNAs provides an exceptional tool for the analysis of gene function. We exploit these advantages with the following two gene systems. (1) The bithorax complex consists of a cluster of genes that act early to select the developmental pathways leading to the thoracic and abdominal segment. We have isolated 200kb of cloned DNA from the bithorax complex, constructed a molecular map of the mutations that define several of its genes, and identified several RNAs transcribed from those genes. The experimental plan for the further definition of the complex is divided into two parts. One is directed toward a further characterization of the gene products of the complex, their distribution in the animal at different times of development, and their function at these times and places; and the other consists in determining the regulation of these regulators--how the genes of the complex are themselves regulated so that different genes are expressed in different founder cells. (2) The second system consists of the regulatory hierarchies that are triggered by the steriod hormone ecdysone to initiate metamorphosis to the adult. We have recently isolated one of the half-dozen """"""""early"""""""" genes that act at the top of the hierarchy in the larval salivary gland and which exhibit a primary response to the hormone. Curiously, this gene is induced by the hormone in several larval and imaginal tissues, indicating that the hierarchies specific to different tissues have overlapping upper ranks. Here again, the experimental plan is divided into two parts: One consisting in the determination of the mechanism by which the steroid hormone induces expression of the early genes, and the other of determining the nature and function of the early gene products in the different hierarchies.
