The juvenile hormones (JHs) are a group of sesquiterpenoids synthesized by the corpora allata. They play critical roles during insect development and reproduction. To study processes that are controlled by JH, researchers need methods to identify and quantify endogenous JHs and tools that can be used to increase or decrease JH titers in vitro and in vivo. The lipophilic nature of JHs, coupled with the low endogenous titers, make handling and quantification challenging. JH titers in insects can easily be increased by the topical application of JH analogs, such as methoprene. On the other hand, experimentally reducing JH titers has been more difficult. New approaches to modulate JH homeostasis have been established based on advances in RNA interference and CRISPR/Cas9-based genome editing. This review will summarize current advances in: (1) the detection and quantification of JHs from insect samples; (2) approaches to manipulating JH titers; and (3) next-generation tools to modulate JH homeostasis.

Biology Centre CAS Institute of Parasitology 370 05 Ceske Budejovice Czech Republic

Department of Biological Sciences and Biomolecular Science Institute Florida International University Miami FL 33199 USA

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Goodman W.G., Cusson M. The Juvenile Hormones. In: Gilbert L.I., editor. Insect Endocrinology. Academic Press; San Diego, CA, USA: 2012. pp. 310–365.

Zhu J., Noriega F.G. The role of juvenile hormone in mosquito development and reproduction. In: Raikhel A., editor. Advances in Insect Physiology. Volume 51. Elsevier; Oxford, UK: 2016. pp. 93–113. Progress in Mosquito Research.

Rivera-Pérez C., Clifton M.E., Noriega F.G., Jindra M. Juvenile hormone regulation and action. In: Saleuddin S., Lange A.B., Orchard I., editors. Advances in Invertebrate (Neuro) Endocrinology. Volume 2. Apple Academic Press, Inc.; Oakville, ON, Canada: 2020. pp. 1–76.

Slama K., Romanuk M., Sorm F. Insect Hormones and Bioanalogues. Springer; New York, NY, USA: 1974.

Cusson M., Sen S.E., Shinoda T. Juvenile hormone biosynthetic enzymes as targets for insecticide discovery. In: Ishayya I., Palli S.R., Horowitz A.R., editors. Advanced Technologies for Managing Insect Pests. Springer; Dordrecht, The Netherlands: 2013. pp. 31–55.

Jindra M., Bittova L. The juvenile hormone receptor as a target of juvenoid “insect growth regulators”. Arch. Insect Biochem. Physiol. 2020;103:e21615. doi: 10.1002/arch.21615. PubMed DOI

Rivera-Perez C., Nouzova M., Noriega F.G. New approaches to study juvenile hormone biosynthesis in insects. Short Views Insect Biochem. Molec. Biol. 2014;7:185–216.

Ramirez C.E., Nouzova M., Benigni P., Quirke J.M.E., Noriega F.G., Fernandez-Lima F. Fast, ultra-trace detection of juvenile hormone III from mosquitoes using mass spectrometry. Talanta. 2016;159:371–378. doi: 10.1016/j.talanta.2016.06.041. PubMed DOI PMC

Bergot B.J., Ratcliff M., Schooley D.A. Method for quantitative determination of the four known juvenile hormones in insect tissue using gas chromatography-mass spectroscopy. J. Chromatogr. 1981;204:231–244. doi: 10.1016/S0021-9673(00)81664-7. DOI

Ramirez C.E., Nouzova M., Michalkova V., Fernandez-Lima F., Noriega F.G. Common structural features facilitate the simultaneous identification and quantification of the five most common juvenile hormones by liquid chromatography-tandem mass spectrometry. Insect Biochem. Molec. Biol. 2020;116:103287. doi: 10.1016/j.ibmb.2019.103287. PubMed DOI PMC

Wigglesworth V.B. The physiology of ecdysis in Rhodnius prolixus (Hemiptera). II. Factors controlling moulting and ‘metamorphosis’. Q. J. Microsc. Sci. 1934;77:191–222.

Villalobos-Sambucaro M.J., Nouzova M., Ramirez C.E., Alzugaray M.E., Fernandez-Lima F., Ronderos J.R., Noriega F.G. The juvenile hormone described in Rhodnius prolixus by Wigglesworth is juvenile hormone III skipped bisepoxide. Sci. Rep. 2020;10:3091. doi: 10.1038/s41598-020-59495-1. PubMed DOI PMC

Dhadialla T.S., Retnakaran A., Smagghe G. Insect growth and development disrupting insecticides. In: Gilbert L.I., Iatrou K., Gill S., editors. Comprehensive Insect Molecular Science. Volume 6. Elsevier/Pergamon; New York, NY, USA: 2005. pp. 55–116.

Jindra M., Palli S.R., Riddiford L.M. The juvenile hormone signaling pathway in insect development. Annu. Rev. Entomol. 2013;58:181–204. doi: 10.1146/annurev-ento-120811-153700. PubMed DOI

Staal G.B. Anti juvenile hormone agents. Annu. Rev. Entomol. 1986;31:391–429. doi: 10.1146/annurev.en.31.010186.002135. DOI

Charles J.-P., Iwema T., Epa V.C., Takaki K., Rynes J., Jindra M. Ligand-binding properties of a juvenile hormone receptor, methoprene-tolerant. Proc. Natl. Acad. Sci. USA. 2011;108:21128–21133. doi: 10.1073/pnas.1116123109. PubMed DOI PMC

Bittova L., Jedlicka P., Dracinsky M., Kirubakaran P., Vondrasek J., Hanus R., Jindra M. Exquisite ligand stereoselectivity of a Drosophila juvenile hormone receptor contrasts with its broad agonist repertoire. J. Biol. Chem. 2019;294:410–423. doi: 10.1074/jbc.RA118.005992. PubMed DOI PMC

Jindra M., Uhlirova M., Charles J.-P., Smykal V., Hill R.J. Genetic evidence for function of the bHLH-PAS protein Gce/Met as a juvenile hormone receptor. PLoS Genet. 2015;11:e1005394. doi: 10.1371/journal.pgen.1005394. PubMed DOI PMC

Clifton M.E., Noriega F.G. Nutrient limitation results in juvenile hormone-mediated resorption of previtellogenic ovarian follicles in mosquitoes. J. Insect Physiol. 2011;57:1274–1281. doi: 10.1016/j.jinsphys.2011.06.002. PubMed DOI PMC

Clifton M.E., Noriega F.G. The fate of follicles after a blood meal is dependent on previtellogenic nutrition and juvenile hormone in Aedes aegypti. J. Insect Physiol. 2012;58:1007–1019. doi: 10.1016/j.jinsphys.2012.05.005. PubMed DOI PMC

Paul A., Harrington L.C., Scott J.G. Evaluation of novel insecticides for control of the dengue vector Aedes aegypti (Diptera: Culicidae) J. Med. Entomol. 2006;43:55–60. doi: 10.1093/jmedent/43.1.55. PubMed DOI

Jones G., Jones D., Li X., Tang L., Ye L., Teal P., Riddiford L., Sandifer C., Borovsky D., Martin J.-R. Activities of natural methyl farnesoids on pupariation and metamorphosis of Drosophila melanogaster. J. Insect Physiol. 2010;56:1456–1464. doi: 10.1016/j.jinsphys.2010.06.001. PubMed DOI

Bowers W.S., Ohta T., Cleere J.S., Marsella P.A. Discovery of insect anti-juvenile hormone in plants. Science. 1976;193:542–547. doi: 10.1126/science.986685. PubMed DOI

Bowers W.S., Martinez-Pardo R. Antiallatotropins: Inhibition of corpus allatum development. Science. 1977;197:1369–1371. doi: 10.1126/science.197.4311.1369. PubMed DOI

Pratt G.E., Jennings R.C., Hamnett A.F., Brooks G.T. Lethal metabolism of precocene-1 to a reactive epoxide by locust corpora allata. Nature. 1980;284:320–323. doi: 10.1038/284320a0. DOI

Tan A., Tanaka H., Tamura T., Shiotsuki T. Precocious metamorphosis in transgenic silkworms overexpressing juvenile hormone esterase. Proc. Natl. Acad. Sci. USA. 2005;102:11751–11756. doi: 10.1073/pnas.0500954102. PubMed DOI PMC

Philpott M.L., Hammock B.D. Juvenile hormone esterase is a biochemical anti-juvenile hormone agent. Insect Biochem. 1990;20:451–459. doi: 10.1016/0020-1790(90)90026-Q. DOI

Bonning B.C., Loher W., Hammock B.D. Recombinant juvenile hormone esterase as a biochemical anti-juvenile hormone agent: Effects on ovarian development in Acheta domesticus. Arch. Insect Biochem. Physiol. 1997;34:359–368. doi: 10.1002/(SICI)1520-6327(1997)34:3<359::AID-ARCH9>3.0.CO;2-P. DOI

Edgar K., Noriega F.G., Bonning B.C., Wells M.A. Recombinant juvenile hormone esterase, an effective tool to modify juvenile hormone-dependent expression of the early trypsin gene in mosquitoes. Insect Molec. Biol. 2000;9:27–31. doi: 10.1046/j.1365-2583.2000.00154.x. PubMed DOI

Kuwano E., Takeya R., Eto M. Terpenoid imidazoles: New anti-juvenile hormones. Agric. Biol. Chem. 1983;47:921–923.

Helvig C., Koener J.F., Unnithan G.C., Feyereisen R. CYP15A1, the cytochrome P450 that catalyzes epoxidation of methyl farnesoate to juvenile hormone III in cockroach corpora allata. Proc. Natl. Acad. Sci. USA. 2004;101:4024–4029. doi: 10.1073/pnas.0306980101. PubMed DOI PMC

Li Y., Kuwano E., Noriega F.G. 1,5-disubstituted imidazoles inhibit juvenile hormone biosynthesis by the corpora allata of the mosquito Aedes aegypti. J. Insect Physiol. 2003;49:1005–1011. doi: 10.1016/S0022-1910(03)00183-5. PubMed DOI

Shinoda T., Itoyama K. Juvenile hormone acid methyltransferase: A key regulatory enzyme for insect metamorphosis. Proc. Natl. Acad. Sci. USA. 2003;100:11986–11991. doi: 10.1073/pnas.2134232100. PubMed DOI PMC

Nouzova M., Michalkova V., Ramirez C.E., Fernandez-Lima F., Noriega F.G. Inhibition of juvenile hormone synthesis in mosquitoes by the methylation inhibitor 3-deazaneplanocin A (DZNep) Insect Biochem. Molec. Biol. 2019;113:103183. doi: 10.1016/j.ibmb.2019.103183. PubMed DOI PMC

Ramos F.O., Leyria J., Nouzova M., Fruttero L.L., Noriega F.G., Canavoso L.E. Juvenile hormone mediates lipid storage in the oocytes of Dipetalogaster maxima. Insect Biochem. Mol. Biol. 2020:103499. doi: 10.1016/j.ibmb.2020.103499. PubMed DOI

Belles X. Beyond Drosophila: RNAi in vivo and functional genomics in insects. Annu. Rev. Entomol. 2010;55:111–128. doi: 10.1146/annurev-ento-112408-085301. PubMed DOI

Whitten M.M.A. Novel RNAi delivery systems in the control of medical and veterinary pests. Curr. Opin. Insect Sci. 2019;34:1–6. doi: 10.1016/j.cois.2019.02.001. PubMed DOI PMC

Meiselman M., Lee S.S., Tran R.T., Dai H., Ding Y., Rivera-Perez C., Wijesekera T.P., Dauwalder B., Noriega F.G., Adams M.E. An endocrine network essential for reproductive success in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA. 2017;114:E3849–E3858. doi: 10.1073/pnas.1620760114. PubMed DOI PMC

Lee S.S., Ding Y., Karapetians N., Rivera-Perez C., Noriega F.G., Adams M.E. Hormonal signaling cascade during an early adult critical period required for courtship memory retention in Drosophila. Curr. Biol. 2017;227:2798–2809. doi: 10.1016/j.cub.2017.08.017. PubMed DOI

Konopova B., Jindra M. Juvenile hormone resistance gene Methoprene-tolerant controls entry into metamorphosis in the beetle Tribolium castaneum. Proc. Natl. Acad. Sci. USA. 2007;104:10488–10493. doi: 10.1073/pnas.0703719104. PubMed DOI PMC

Minakuchi C., Namiki T., Shinoda T. Kruppel homolog 1, an early juvenile hormone-response gene downstream of Methoprene-tolerant, mediates its anti-metamorphic action in the red flour beetle Tribolium castaneum. Dev. Biol. 2009;325:341–350. doi: 10.1016/j.ydbio.2008.10.016. PubMed DOI

Konopova B., Smykal V., Jindra M. Common and distinct roles of juvenile hormone signaling genes in metamorphosis of holometabolous and hemimetabolous insects. PLoS ONE. 2011;6:e28728. doi: 10.1371/journal.pone.0028728. PubMed DOI PMC

Villalobos Sambucaro M.J., Riccillo F.L., Calderón-Fernández G.M., Sterkel M., Diambra L.A., Ronderos J.R. Genomic and functional characterization of a methoprene-tolerant gene in the kissing-bug Rhodnius prolixus. Gen. Comp. Endocrinol. 2015;216:1–8. doi: 10.1016/j.ygcen.2015.04.018. PubMed DOI

Saha T.T., Roy S., Pei G., Dou W., Zou Z., Raikhel A.S. Synergistic action of the transcription factors Kruppel homolog 1 and Hairy in juvenile hormone/Methoprene-tolerant-mediated gene-repression in the mosquito Aedes aegypti. PLoS Genet. 2019;15:e1008443. doi: 10.1371/journal.pgen.1008443. PubMed DOI PMC

Noriega F.G., Shaa D., Wells M.A. Juvenile Hormone controls early trypsin gene expression in the midgut of Aedes aegypti. Insect Molec. Biol. 1997;6:63–66. doi: 10.1046/j.1365-2583.1997.00154.x. PubMed DOI

Li M., Mead E.A., Zhu J. Heterodimer of two bHLH-PAS proteins mediates juvenile hormone-induced gene expression. Proc. Natl. Acad. Sci. USA. 2011;108:638–643. doi: 10.1073/pnas.1013914108. PubMed DOI PMC

Zhao B., Hou Y., Wang J., Kokoza V.A., Saha T.T., Wang X.-L., Lin L., Zou Z., Raikhel A.S. Determination of juvenile hormone titers by means of LC-MS/MS/MS and a juvenile hormone-responsive Gal4/UAS system in Aedes aegypti mosquitoes. Insect Biochem. Mol. Biol. 2016;77:69–77. doi: 10.1016/j.ibmb.2016.08.003. PubMed DOI PMC

Perkins L.A., Holderbaum L., Tao R., Hu Y., Sopko R., McCall K., Yang-Zhou D., Flockhart I., Binari R., Shim H.-S., et al. The transgenic RNAi project at Harvard medical school: Resources and validation. Genetics. 2015;201:843–852. doi: 10.1534/genetics.115.180208. PubMed DOI PMC

Sun D., Guo Z., Liu Y., Zhang Y. Progress and prospects of CRISPR/Cas systems in insects and other arthropods. Front. Physiol. 2017;8:608. doi: 10.3389/fphys.2017.00608. PubMed DOI PMC

Deltcheva E., Chylinski K., Sharma C.M., Gonzales K., Chao Y., Pirzada Z.A., Eckert M.R., Vogel J., Charpentier E. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature. 2011;471:602–607. doi: 10.1038/nature09886. PubMed DOI PMC

Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J.A., Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–821. doi: 10.1126/science.1225829. PubMed DOI PMC

Huynh N., Wang S., King-Jones K. Spatial and temporal control of gene manipulation in Drosophila via drug-activated Cas9 nucleases. Insect Biochem. Mol. Biol. 2020;120:103336. doi: 10.1016/j.ibmb.2020.103336. PubMed DOI

Daimon T., Uchibori M., Nakao H., Sezutsu H., Shinoda T. Knockout silkworms reveal a dispensable role for juvenile hormones in holometabolous life cycle. Proc. Natl Acad. Sci. USA. 2015;112:E4226–E4235. doi: 10.1073/pnas.1506645112. PubMed DOI PMC

Zhang Z., Liu X., Shiotsuki T., Wang Z., Xu X., Huang Y., Tan A. Depletion of juvenile hormone esterase extends larval growth in Bombyx mori. Insect Biochem. Mol. Biol. 2017;81:72–79. doi: 10.1016/j.ibmb.2017.01.001. PubMed DOI

Wen D., Rivera-Perez C., Abdou M., Jia Q., He Q., Zyaan O., Bendena W.B., Tobe S.S., Noriega F.G., Palli S.R., et al. Methyl farnesoate plays a dual role in regulating Drosophila metamorphosis. PLoS Genet. 2015;11:e1005038. doi: 10.1371/journal.pgen.1005038. PubMed DOI PMC

Guan-Heng Zhu G.-H., Jiao Y., Chereddy S.C.R.R., Noh M.Y., Palli S.R. Knockout of juvenile hormone receptor, Methoprene tolerant, induces black larval phenotype in the yellow fever mosquito, Aedes aegypti. Proc. Natl. Acad. Sci. USA. 2019;116:21501–21507. PubMed PMC

Kim I.H., Castillo J.C., Aryan A., Martin-Martin I., Nouzova M., Noriega F.G., Barletta A.B.F., Calvo E., Adelman Z.N., Ribeiro J.M., et al. A mosquito juvenile hormone binding protein (mJHBP) regulates the activation of innate immune defenses and hemocyte development. PLoS Pathog. 2020;16:e1008288. doi: 10.1371/journal.ppat.1008288. PubMed DOI PMC

Effects of mating on female reproductive physiology in the insect model, Rhodnius prolixus, a vector of the causative parasite of Chagas disease

Crosstalk between Nutrition, Insulin, Juvenile Hormone, and Ecdysteroid Signaling in the Classical Insect Model, Rhodnius prolixus