Rheb, a key component of the amino acid signaling pathway, controls mosquito egg development

Mosquitoes cause more human suffering than any other arthropod vector -- over one million people die from mosquito-borne diseases every year. The anautogenous female mosquito feeds on vertebrate blood to initiate its reproductive cycle. Whereas this strategy is important for driving disease transmission, the molecular mechanisms underlying this phenomenon are still not clearly understood. The synthesis of yolk protein precursors (YPP's), a central event in egg maturation, occurs inside the mosquito fat body. Our laboratory had previously reported that amino acid signaling through the nutrient sensitive target of rapamycin (TOR) pathway is essential for the activation of the YPP gene expression. In this study, we demonstrate that the Ras homologue enriched in brain (Rheb) is required for the activation of the TOR pathway in the fat body of the mosquito Aedes aegypti. dsRNA mediated Rheb knockdown resulted in severe down-regulation of the major YPP gene, vitellogenin (Vg) . Knock-down of the Ae. aegypti Rheb also lead to the complete inhibition of S6 kinase phosphorylation, one of the major downstream target molecules of TOR, in the fat body, after being stimulated with amino acids. Depletion of Rheb by RNAi resulted in the inhibition of Vg transcription as well as translation, both in vitro and in vivo. Finally, we show that Rheb knockdown inhibits egg development in vivo. A better understanding of how this intricate signaling process is regulated at the molecular level could lead to safe, specific and effective way to block reproduction in blood feeding insects.