Molecular Basis of Ecdysteroid Action in the Mosquito

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Abstract: Hematophagous female mosquitoes transmit numerous devastating diseases, while feeding on human blood. A large enough blood-meal is essential for the development of eggs in a female mosquito, thereby interlinking reproduction, blood-feeding and pathogen transmission. Therefore, a clear understanding of the molecular mechanisms regulating egg development can play a critical role in advancement of mosquito control methods. In Aedes aegypti, the Dengue-, Zika- and Yellow fever- transmitting mosquito, two major insect hormones - the juvenile hormone (JH) and the 20-hydroxyecdysone (20E), control the biphasic female mosquito reproductive cycle. The post eclosion (PE) or the pre-vitellogenic maturation phase is under the control of JH, a sesquiterpenoid. Whereas, the post blood meal (PBM) or the vitellogenic phase is mostly controlled by the ecdysteroid, 20E. Some aspects of the molecular basis of JH action has been deciphered in recent times. However, studies on the role of the intermediate factors within the JH/Met regulatory cascade, are ongoing. Gene activation by JH, in most cases, is mediated by direct DNA binding of the JH-receptor Methoprene-tolerant (Met). However, the repression mechanism by JH is indirect, through intermediate factors. This proposal is aimed towards further elucidation of the JH mediated gene activation and repression cascades. Investigation of the role of Krüppel homolog 1(Kr-h1), as a downstream factor of Met in mediating gene repression, and its cooperative action with the long-range repressor Hairy, will be one of the primary foci. The proposed comparative analysis of the chromatin landscapes of JH pathway target genes, should determine the contributions of the components such as Met, Hairy and Kr-h1, on the chromatin states of the target genes. Most studies, on the mechanism of 20E action, have focused on positive gene regulation through the Ecdysone Receptor (EcR). This proposal, is aimed mainly at deciphering the role of 20E and EcR in the previously unexplored area of negative gene regulation, during the vitellogenic period. We plan to elucidate the mechanism of direct and indirect negative regulation and identify co-repressor(s) and intermediate factor(s) of the 20E/EcR-mediated gene repression pathway. This study should potentially lead to identification of targets that can either be blocked or transformed to achieve reproductive control in female mosquitoes, thereby reining blood feeding and pathogen transmission.