Juvenile hormone is what prevents an insect from spreading its wingstoo soon. Instead, the subtle molecule keeps the bug in its larval stages,through several moltings, before disappearing. Only then can the larvametamorphose from, say, a leaf-munching caterpillar into a flower-sipping moth.For at least a quarter of a century, juvenile hormone (JH) has ledcommercial and academic entomologists on a merry chase for nature'sideal insecticide. Early on, the researchers found that by keeping larvaesupplied with a steady diet of JH, they could stall metamorphosis untilthe grub grew to monstrous size, and died of its own weight.[For more on JH's improbable, serendipitous history, see the story onpage 4.]Only one JH variant, Switzerland-based Sandoz Corp.'s methoprene,has reached extensive commercialization. "It commands only about 5percent of the market," University of Nevada insect biochemist DavidSchooley told BioWorld Today. It's used against mosquito larvae,cockroaches and for controlling fleas.Farmers in Australia, said insect endocrinologist Lynn M. Riddiford,must resort to methoprene for protecting their stored grain from insectpests, "because these are now resistant to all insecticides, including thepyrethroids."Another putative application for methoprene is to incorporate it in saltblocks on which cattle feed. It would go through the gut and out infeces, on which stable flies lay their eggs. Those larvae would nevermetamorphose.Other versions of JH, Riddiford told BioWorld Today, have proven tooexpensive to be widely commercialized, although companies such asAmerican Cyanamid, Ciba-Geigy and Sumitomo are pursuing researchto develop potent JH analogs.JHs Work All Too WellRiddiford, who teaches zoology at the University of Washington inSeattle, explained that a crucial limitation of JH analogs is that theywork all too well in Lepidoptera _ gypsy moths, corn borers and thelike. "If you use JH on these crop pests," she explained, "you prolongthe larva's life, so it eats more. Once it dies, of course, you don't havemoths the next year, but farmers don't like it."So Riddiford's laboratory has taken a lead in seeking to solve the riddleof how JH works at the molecular level. Her latest paper, in the June 21issue of Proceedings of the National Academy of Sciences (PNAS), istitled: "A nuclear juvenile hormone-binding protein from larvae ofManduca sexta: A putative receptor for the metamorphic action ofjuvenile hormone."Manduca sexta is the tobacco hornworm, which Riddiford calls "thelaboratory rat of insect endocrinology." It's a model for similar pests ofgreater economic significance, such as the tomato hornworm.To find out how JH prevents metamorphosis, she said, "in this day andage of molecular biology, you go down to the cell to see how,somehow, it is guiding the action of ecdysin, the steroid hormone thatcauses molting and metamorphosis."In the past five years, she explained, researchers have found that theecdysin receptor complex binds directly to the DNA of transcriptionfactor genes, and turns them on. "Then those factors can turn othergenes either on or off."Jointly with collaborators at three other university labs - SUNY inStony Brook, California in Davis, and Wisconsin in Madison _ shehas isolated and cloned a 29-kiloDalton protein that binds JH [deleteanalog] but only in the cell nucleus."This 29kD protein," Riddiford said, "which we have just reported inPNAS, displayed a developmental time course. That is, it was presentduring the larval stages, when JH was present. And it was present at thetime ecdysin triggered the molt, which is critical, because this decideswhether its going to be another larva, or metamorphose." Then, sheadded, "29kD disappeared from the larva's epidermis at the time thisbecomes committed at the end of larval life."What next? "Two things: "We are trying to find this JH-binding proteinin the fruit fly, Drosophila melanogaster, so we can use genetics to tellus really what its function is."Second, her lab will "go directly and look at 29kD's role in thenucleus, something that the protein's cDNA sequence didn't give usany clues to."A hoped-for outcome of this research, Riddiford suggests, "if we canlearn more about this protein, and how it works in the nucleus, then onecould target that protein or that function, whatever it is, as anantagonist to JH. The pest would still be making its JH, but thiswouldn't work on its target cell _ whatever that was."Nevada's Schooley said of Riddiford's latest work, "Her receptor is anunusual type that hopefully will explain how JH works in insect larvae.Being able to produce this receptor by recombinant-DNA technology,would make possible very rapid testing for JH and antagonist activity."Actually, Schooley added, "JH antagonists would be much morecommercially useful than JHs. JHs are only useful for controlling theadult portion of the insect population, which is why they are only aminor segment of the total insecticide market. If you had an antagonistthat would block the action of JH, this would cause insects toprematurely develop into pupae, on their way to metamorphosis, andstop doing damage to crops." n

-- David N. Leff Science Editor

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