Genetic and pharmacological approaches demonstrate extrinsic regulation of oogenesis in Drosophila melanogaster

Development involves the coordinated and tightly regulated expression of many genes that govern the formation of a complex organism from a single cell. Such an intricate program can be error prone; morphogenetic defects can result from alterations in developmental processes caused by genetic lesion or environmental agents. Simple models, such as the fruit fly Drosophila melanogaster, have aided in the elucidation of many genes involved in morphogenesis in many organisms. In this work, we have used Drosophila oogenesis as a developmental model to study the effects of one particular harmful environmental agent, namely cocaine. This model represents a unique opportunity to discover new regulation of oogenesis, as well as new molecular effects of chronic cocaine exposure. We have uncovered previously unrecognized signaling mechanisms that function outside the ovary, but have effects on oogenesis.; Our work implicates multiple signaling mechanisms in the extrinsic regulation of oogenesis. First, ovary transplantation has revealed that the stall gene is required in tissues outside of the ovary for proper follicle formation. Although it has been recognized that ovary nonautonomous signals are critical for follicle maturation and survival, this study is the first demonstration of such regulation of the early stages of follicle formation. In addition to stall-mediated regulation, we have uncovered a cocaine-sensitive role for serotonin and juvenile hormone signaling in ovarian follicle formation. During our examination of the effects of chronic cocaine exposure on oogenesis, we found that dopamine signaling is critical for the regulation of follicle maturation and survival, since perturbing this pathway by either cocaine or dopamine feeding results in apoptosis of follicles. Further analysis of this model has identified dopamine signaling as an important regulator of steroid hormone synthesis in adult females. Finally, since serotonin and dopamine are not detected in the ovary and neural projections are not found in the region of the ovary where follicles are produced, we conclude that oogenesis regulatory roles of these pathways are critical in neural tissue outside of the ovary. These studies have important implications for the future study of not only cocaine response, but also oogenesis and development in many species.