Mosquitoes are insect vectors responsible for the transmission of many infectious diseases to hundreds of millions of people worldwide. Females of most mosquito species require blood from vertebrate animals for their egg development. Multiple bloodfeedings enable mosquitoes to transmit disease pathogens, including malaria parasites and dengue virus, from one person to another. Our long term goal of this project is to elucidate the molecular mechanisms that regulate mosquito egg production and identify target molecules that can be utilized for mosquito control. Mosquito egg development is governed by alternating peaks of two major insect hormones - juvenile hormone (JH) and 20-hydroxyecdysone (20E). Deprivation of JH in newly emerged adult female mosquitoes will halt egg maturation. On the other hand, topical application of JH to mosquitoes shortly after blood feeding interferes with the normal responses to 20E and impairs egg production. We have recently demonstrated that the mosquito Methoprene-tolerant (AaMet) protein is a key player in the juvenile hormone signaling pathway in the newly emerged adult female mosquitoes. AaMet protein binds to JH and forms a complex with AaFISC protein, a coactivator of the 20E receptor. AaMet and AaFISC are found to be associated with the promoters of JH target genes and activate their expression. In addition, our preliminary studies imply that AaMet mediates the inhibitory effects of JH on 20E-induced gene expression. Taken together, the results suggest that AaMet and AaFISC are components of a juvenile hormone receptor. The objective of this project is to elucidate the molecular details of how AaMet functions in juvenile hormone signaling that regulates egg maturation in mosquitoes.
In Aim 1, we will perform structure-function studies of the juvenile hormone binding domain in AaMet and define the structural determinants required for high affinity binding to JH.
In Aim 2, we will investigate how AaMet and AaFISC proteins are recruited to juvenile hormone response elements in the JH target genes.
In Aim 3, we will test the hypothesis that AaMet is involved in the crosstalk between juvenile hormone and 20E signals in blood-fed female mosquitoes. The study will significantly advance our understanding of the molecular action of juvenile hormone in mosquitoes, and provide a structural basis for designing new pesticides that specifically target the mosquito JH signaling pathway.

Public Health Relevance

The goal of this study is to elucidate the molecular mechanism by which the mosquito juvenile hormone regulates egg maturation in adult female mosquitoes. A better understanding of the hormone action at the molecular level is of paramount importance for designing new mosquito pesticides that specifically block the action of juvenile hormone, potentially disrupting all the biological processes in mosquitoes that are regulated by juvenile hormone.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vector Biology Study Section (VB)
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Costero, Adriana
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Virginia Polytechnic Institute and State University
Schools of Earth Sciences/Natur
United States
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Liu, Pengcheng; Fu, Xiaonan; Zhu, Jinsong (2018) Juvenile hormone-regulated alternative splicing of the taiman gene primes the ecdysteroid response in adult mosquitoes. Proc Natl Acad Sci U S A 115:E7738-E7747
Ojani, R; Fu, X; Ahmed, T et al. (2018) Kr├╝ppel homologue 1 acts as a repressor and an activator in the transcriptional response to juvenile hormone in adult mosquitoes. Insect Mol Biol 27:268-278
Ojani, Reyhaneh; Liu, Pengcheng; Fu, Xiaonan et al. (2016) Protein kinase C modulates transcriptional activation by the juvenile hormone receptor methoprene-tolerant. Insect Biochem Mol Biol 70:44-52
Liu, Pengcheng; Peng, Hong-Juan; Zhu, Jinsong (2015) Juvenile hormone-activated phospholipase C pathway enhances transcriptional activation by the methoprene-tolerant protein. Proc Natl Acad Sci U S A 112:E1871-9
Li, Meng; Liu, Pengcheng; Wiley, Jessica D et al. (2014) A steroid receptor coactivator acts as the DNA-binding partner of the methoprene-tolerant protein in regulating juvenile hormone response genes. Mol Cell Endocrinol 394:47-58