Chemistry Of Juvenile Hormones

The juvenile hormones are lipophilic sesquiterpenoid derivatives of farnesoic acid. Their chemical nature came into focus in the early 1960s, beginning with observations that farnesoid components of beetle excreta had JH-like activity in bioassays. Although far less potent than the native hormone, these substances, including farnesol and its oxidized form farnesal, were suspected to be JH precursors. Subsequent synthesis of methyl farnesoate with an epoxide at position 10—11 by William Bowers in 1965 gave a highly potent compound. It is indeed ironic that this compound was discovered 8 years later to be the most ubiquitous of the natural juvenile hormones, JH-III (Fig. 2).

Another interesting prologue to the discovery of the natural juvenile hormones was the discovery of a curious

FIGURE 2 Structures of natural juvenile hormones and related compounds. Juvabione is the paper factor from North American balsam fir discovered by Williams, Slama, and Bowers. JH-I was the first natural JH discovered by Roller, and JH-II and JH-III soon followed. JH-III is present in most groups of insects, including the Lepidoptera. JH-0 is found in moth eggs, but its biological function is unclear. JH-0, JH-I, and JH-II are generally confined to the Lepidoptera. Methyl farnesoate, a JH precursor, has been isolated from some insects and crustaceans, in which it may serve as the active JH.

FIGURE 2 Structures of natural juvenile hormones and related compounds. Juvabione is the paper factor from North American balsam fir discovered by Williams, Slama, and Bowers. JH-I was the first natural JH discovered by Roller, and JH-II and JH-III soon followed. JH-III is present in most groups of insects, including the Lepidoptera. JH-0 is found in moth eggs, but its biological function is unclear. JH-0, JH-I, and JH-II are generally confined to the Lepidoptera. Methyl farnesoate, a JH precursor, has been isolated from some insects and crustaceans, in which it may serve as the active JH.

"paper factor" by Karel Slama and Carroll Williams in the mid-1960s. Slama had carried insects from his laboratory in Czechoslovakia to the laboratory of Williams at Harvard University for a series of joint experiments. Some weeks after arriving the insects began to develop extra stages and many died. Nothing of the sort was noticed in Czechoslovakia. It was eventually determined that the paper towels used to line the containers holding the insects contained compounds with JH-like biological activity. The substances were absorbed through the insect cuticle upon contact with the paper towels. The paper factor turned out to be a mixture of terpenoids in the wood pulp from which the paper towels were manufactured. These compounds were found only in American and Canadian balsam fir and not in European trees. One of these substances was chemically identified by Bowers and colleagues as "juvabione" (Fig. 2), which had a structure reminiscent of farnesol.

These studies provided new information on two critical issues of the time. First was the question of juvenile hormone structure. Observations that farnesol and methyl farnesoate, along with juvabione, possessed JH-like biological activity made it likely that terpenoid chemistry was involved. This guided further attempts to chemically define the natural material(s). The second issue was whether juvenile hormones or analogs such as juvabione could be used to produce, as Carroll Williams suggested, a new class of "third-generation" pesticides. Juvabione constituted a relatively stable terpenoid with potent insecticidal activity and hence stimulated further interest in this novel concept for new insecticides that would be both highly insect-selective and safe for warm-blooded animals.

With this as background, Roller and colleagues isolated sufficient quantities of juvenile hormone from silk moth abdomens for identification of the first natural juvenile hormone in 1967. The carbon skeleton was identified as a 15-carbon sesquiterpene substituted at positions 7 and 11 with ethyl groups. Further key structural features were the presence of a methyl ester and an epoxide at carbons 10—11. This landmark achievement was followed rapidly by publication of a second JH, also from moths. These molecules were named JH-I and JH-II, respectively, differing only at carbon 7, which was ethylated in JH-I and methylated in JH-II (Fig. 2). These two juvenile hormones are largely restricted to the Lepidoptera. Within a few years, a third hormone was identified by a completely different approach. In this instance, corpora allata from the moth Manduca sexta were removed and placed in organ culture containing a radiolabeled methyl donor, 14C-labeled methionine. The corpora allata incorporated the 14C-methyl group into the ester moiety of juvenile hormone. This isotope-labeled synthetic product was isolated and identified as JH-III. It is the most cosmopolitan of juvenile hormones, occurring in most insect groups, including the Lepidoptera. It has methyl groups at positions 7 and 11 (Fig. 2). Three additional JH structures have been identified: JH-0 and 4-methyl JH from moth eggs and JH-bisepoxide from the fruit fly Drosophila.

The juvenile hormones are derived from acetyl CoA and/or propionyl CoA via mevalonic acid and homomevalonic acid in the sterol biosynthetic pathway. The final steps of JH-III biosynthesis go by way of farnesol ^ farnesoic acid ^ methyl farnesoate, to which an epoxide is formed at carbons 10—11. Owing to their low aqueous solubility, the juvenile hormones are transported through the blood via binding proteins upon their release from the corpora allata. These binding proteins also protect JH from degradative enzymes.

In some insects, the corpora allata synthesize a precursor of the biologically active form of JH, which is converted to the active form in target tissues. For example, silk moth adults produce JH acid in the corpora allata and convert it to JH-I in the accessory glands of the abdomen. It is also known that the ovaries of certain species of mosquito can synthesize JH from precursors under culture conditions. Whether this occurs under natural conditions in vivo has not been demonstrated.

The levels of JH in the blood are regulated through a combination of synthesis and degradation. Synthesis by the corpora allata is promoted by neuropeptides called allatropins. So far, only one allatotropin has been identified from the tobacco hawkmoth M. sexta. Surprisingly, the peptide is active only in the adult stage. More compelling evidence has been provided for the existence of allatostatins. These are neuropeptides synthesized in brain neurons that project to the corpora allata. Their release from nerve endings in the gland inhibits the synthesis of juvenile hormone.

The removal of juvenile hormones already in the blood, a necessary condition for metamorphosis, occurs through two enzymatic degradation pathways. One is through cleavage of the ester bond by JH esterase, the other through epoxide destruction by epoxide hydrolases.

BIOLOGICAL ACTIONS Morphogenetic Effects

The presence of juvenile hormones in the blood promotes expression of juvenile characters, chief among these being an immature body form or morphology. For insects such as grasshoppers, which undergo incomplete metamorphosis, the effects are not so visible outwardly. The early stages look like miniature adults except for the absence of wings, but they also lack functional reproductive organs. However, for those insects such as flies, moths, and bees, which undergo complete metamorphosis, the effects are extreme. The immature stages are wormlike with no wings or legs.

Determination of holometabolous immature or larval body plan by juvenile hormone represents its morphogenetic action. The decision to develop larval characters during development is made near the end of each larval stage, when ecdysteroid levels increase to initiate the molt. Elevation of ecdysteroids causes a cessation of feeding and new round of gene expression appropriate for the next stage of development. If juvenile hormones are present at this time, genes for larval characters are expressed, whereas genes appropriate for pupal or adult characters are repressed. A primary larval character is the type of cuticle secreted by the epidermal cells. Larval cuticle is lighter and more flexible than pupal or adult cuticle, which are characteristics resulting from expression of larval cuticle protein genes that predominate under the influence of juvenile hormones. The flexibility of larval cuticle has to do with the absence of cross-linking between proteins and between proteins and chitin, the latter constituting the polysaccharide component of the cuticle. In contrast, pupal and adult cuticles are hard and dark, indicating a high degree of sclerotization and melanization.

Specification of pupal or adult features by JH, or lack thereof, is associated with transient, hormone-sensitive periods during development. It is important to note that the actions of JH depend not only on its presence in the blood, but also on the ability of cellular targets to respond. This latter condition presumably reflects the presence of suitable receptors required to mediate the action of the hormone. It has been observed in many studies that JH responsiveness occurs after priming, which could be associated with expression of receptor genes or other molecules necessary to complete the signaling pathway. For example, in moths, specification of a wandering period in preparation for pupation occurs upon the appearance of ecdysteroid peaks in the complete absence of JH. These "commitment" peaks of ecdysteroid prime the system to respond later in the same stage to elevated JH levels, which specify pupal features.

In many insects, considerable development of the gonads takes place during the larval stages. This is especially true for insects such as the silkworm Bombyx mori, which does not feed during the adult stage. Within hours of emergence, these animals mate and lay eggs. The ability to mate and produce viable eggs so soon after emergence means that gonadal development is well along during the larval and pupal stages. Juvenile hormones promote the development of gonads and gametes during the immature stages, but must disappear in order for final developmental steps to be completed. This drop in JH levels just prior to the pupal stage therefore serves both morphogenetic and gonadotropic functions.

Effects of JH in the Adult Stage

The decrease in JH levels just prior to metamorphosis is only a temporary condition. The corpora allata are retained in the adult stage, and JH eventually reappears to regulate adult reproductive functions. JH promotes sperm and egg development and hence is said to have "gonadotropic" functions. In the female, JH directly promotes the synthesis of lipo- and glycoproteins in the fat body and their uptake into the developing oocyte. This process, called vitellogenesis, is essentially yolk deposition. In many insects, JH levels rise and fall in a cyclic fashion as discrete batches of oocytes go through the vitellogenic process.

In other instances, as in some mosquitos, JH exposure leads to "competence" of the fat body to synthesize vitellogenic proteins upon later exposure to ecdysteroids. Likewise, JH exposure is required to induce competence of the ovaries to respond later to peptide hormones from the nervous system, thus stimulating uptake of vitellogenic proteins. In these instances, the gonadotropic actions of JH appear to be priming steps in preparation for ecdysteroid action.

Gonadotropic functions of JH in the male have to do with growth of the sperm. Sperm growth requires JH in many insects. However, maturation from spermatocytes to motile spermatids requires a drop in JH. As observed for oocyte development, JH exerts both positive and negative influences in sperm development.

Polyphenism and Caste Determination

Many insects have the remarkable ability to develop into alternate forms as they become adults. These alternate forms together with accompanying physiology and behavior, referred to as polyphenism, do not reflect differences in the genetic makeup of individuals. Rather, they result from a particular pattern of gene expression under hormonal control. Most polyphenisms are controlled by juvenile hormones acting at certain sensitive periods during immature development.

Some of the most common instances are caste polyphenisms observed in social insects such as bees, ants, and termites. In these insect societies, larvae can develop into workers, soldiers, or queens, depending on the diet they are raised on and the hormonal levels that result. If bee larvae are reared in a special cell in the hive and consistently fed a nutritious "royal jelly" beginning during the third instar, they develop into queens.

Treatment with JH will mimic this effect. If this feeding is delayed, larvae develop into workers instead. In certain ants, development of queens is regulated during embryonic development by JH levels. During postembryonic development, larvae fed a high-protein diet produce large amounts of JH, bringing blood levels to a threshold necessary for specification of soldier phenotype. If larvae are fed a diet lower in protein, JH levels are correspondingly lower, and development to worker is specified. The number of soldiers in the colony also is determined by a soldier-inhibiting pheromone, which elevates the JH threshold for soldier specification. Alternative body forms and behaviors in insect colonies provide for cooperative functions between members of the society to serve the greater whole.

Many types of phase polyphenisms occur in nonsocial insects. For example, locusts occur either in solitary or in migratory phases, depending on population density. Differences in both behavior and physiology are characteristic of these phases. Solitary locusts are sedentary, pale green, yellow, or brown, and have short wings and large ovaries. Crowding causes the switch to the gregarious phase, in which individuals are brightly colored, have longer wings and smaller ovaries, and are easily induced to engage in long flights. Both JH and peptide neurosecretory hormones from the brain are involved in the determination of these two phases.

Aphids exhibit at least two different types of phase poly-phenism as a response to seasonal conditions: food quality and crowding. In one type, adults switch between winged or apterous (no wings) forms. The other type has to do with the mode of reproduction, either sexual or parthenogenetic. During the longer days of spring and summer, apterous, parthenogenetic females predominate, and juvenile hormone is involved in specification of these forms. As winter approaches, winged forms are produced, allowing for dispersal. Later, in autumn, males and females mate and lay eggs, which overwinter and hatch in the spring. In this context, body forms and accompanying dispersal or migratory behaviors maximize survival as the season changes.

In summary, JH and other neurosecretory hormones are important determinants of polyphenisms, which result in different body forms, reproductive physiologies, and behaviors in the adult stage. It is emphasized that such variability of form and function is not the result of genetic differences between individuals, which would be classified as polymorphisms. Rather, insects have the enormous potential to change form in response to environmental conditions through hormonal control mechanisms. Depending on the needs of a social colony, or changes of season and in food availability, the complex endocrinology of insects enables them to assume various alter egos to enhance success and survival.

Behavioral Effects of JH

The presence or absence of juvenile hormones has profound effects on behavior, some of which have been mentioned above. Throughout the stages of immature development, JHs program gene expression in the nervous system for the expression of behaviors appropriate for juvenile life, including, for example, locomotion, host or prey seeking, feeding, and silk spinning. From the point of view of behavior, the larva is an animal completely different from its later adult form.

In moths, the disappearance of JH at the end of the last instar allows ecdysteroids to program new behaviors appropriate for metamorphosis. Insects stop feeding, void their guts, and engage in wandering behaviors to locate a suitable pupation site. This accomplished, a series of behaviors leads to silk spinning for cocoon construction.

Upon becoming adults, female mosquitos initiate the search for a blood meal and become sexually receptive to males only after release ofJH into the blood. In milkweed bugs, JH levels are influenced by daylength, temperature, and food quality. Under short daylengths, JH levels drop, and insects engage in migratory behavior immediately after molting to the adult stage. However, long days and warm conditions lead to high JH levels, whereby flight is inhibited and reproduction ensues.

Grasshopper females that have had corpora allata removed rebuff male sexual advances until JH is reintroduced by injection. In crickets, the male sings a species-specific calling song to attract the female for mating. The female responsiveness to this song is enhanced by elevated JH levels. These examples serve to illustrate the dramatic effects that JH has on the behavior of insects, effects that are specific and appropriate for each particular life stage.

Dormancy—Diapause

Insects are able to enter prolonged states of dormancy referred to as diapause, allowing them to resist freezing and low food supplies during the winter. Diapause can occur at any stage (egg, larva, pupa, or adult) and is triggered by decreasing daylength, low temperatures, decreased food or food quality, or a combination of these factors. The insect response to these environmental factors is mediated by a variety of hormones, depending on the stage and species.

Adult diapause is largely synonymous with reproductive diapause. Beetles, butterflies, and flies enter a reproductive diapause when the brain inhibits synthesis of JHs by the corpora allata. The lack of JHs leads to both physiological and behavioral changes, including cessation of vitellogenesis, loss of flight muscle, increasing stores of lipid in the fat body, burrowing, and construction of hibernacula (overwintering chambers). Implantation of corpora allata or injection of JHs reverses reproductive diapause.

JH involvement in larval diapause also has been documented. The southwestern corn borer Diatraea grandiosella enters diapause during the last instar when JH levels are depressed but are still high enough to inhibit development to the pupal stage. The animal spins a hibernaculum, exhibits a light pigmentation, and actually undergoes several "stationary" molts. Diapause in this stage lasts as long as JH levels remain elevated.

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