HORMONAL CONTROL OF GENETIC HIERARCHIES IN DEVELOPMENT

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The long-term objective of the proposed research is to determine the molecular genetic mechanisms by which steroid hormones control tissue development. This is a general problem in higher animals including humans, and is of particular importance to an understanding of the role steroid hormones play in the generation of cancers. More specifically, this research is directed toward the molecular definition of the genetic regulatory hierarchies that effect the coordination of the developmental pathways of a set of tissues in response to a steroid hormone. Drosophila melanogaster is the preferred organism for these studies because it includes the only example among higher animals of a well defined steroid-activated genetic regulatory hierarchy. This hierarchy is manifested by the program of polytene chromosome puffing induced in the larval salivary glands by a pulse of the steroid hormone ecdysone at the end of larval life - a pulse that initiates metamorphosis to the adult fly by inducing a coordinated change in the developmental pathways of a set of target tissues. The model proposed by Ashburner for the generation of these transcription puffs consists of a genetic hierarchy of at least three ranks. Starting with the gene encoding the ecdysone receptor protein, the transcription of a half-dozen "early" regulatory genes responsible for the first set of puffs is induced by the ecdysone-receptor complex. Proteins encoded by these early genes then induce the transcription of a much larger set of genes responsible for the next set of puffs. The cloning and characterization of the ecdysone receptor gene (EcR) and two of the early genes (E74, E75) in this laboratory have yielded results consistent with the Ashburner model and indicate that genetic regulatory hierarchies akin to that proposed by Ashburner may also govern the ecdysone response of the other target tissues involved in metamorphosis. The resulting "tissue coordination model" proposes that the third rank in these related tissue-specific hierarchies consists of "effector" genes which effect the change in the tissue's morphological and functional properties that constitute the next step in its developmental pathway. The experimental plan is directed toward the testing and further development of this model. In the first phase, the distribution of E74 and E75 expression among the target tissues, and the role played by the EcR gene in generating that distribution, will be determined. Subsequently, other early genes will be cloned and similarly characterized, followed by the cloning of genes regulated by the early gene proteins in particular target tissues and the testing of these genes for effector properties. Mutational studies will also be used to determine the interaction among the genes in these hierarchies.