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Regulation of Developmental Timing

Another important aspect of development is that regulatory processes must be properly timed so that cell growth and differentiation are appropriate for the particular life stage of the animal. In humans, for example, the transition from adolescence to adulthood is accompanied by rapid changes in growth and acquisition of sexual maturity. Likewise, in insects developmental transitions also occur at regularly defined intervals. These transitions include molting, a processes whereby the rigid exoskeleton is shed and re-synthesized to accommodate increasing body size as a result of cell growth, and metamorphosis, a stunning transformation in which the immature larva changes into the reproductively mature adult. In both cases (human and insect) these changes are mediated to a large extent by small circulating steroid hormones that bind and activate transcription factors of the nuclear receptor superfamily. In many arthropods, 20-hydroxyecdysone (20E), is the primary active steroid hormone that coordinates developmental transitions. Although the genetic hierarchy that controls responses to 20E has received considerable attention, little is presently known about the genes involved in ecdysteroid biosynthesis and regulatory mechanisms that control hormone production.
We are interested in elucidating the mechanisms that regulate ecdysone biosynthesis and degradation as a means of gaining insight into the issue of developmental timing. Since ecdysone is required to produce new cuticle at the various larval molts, we focused our attention on a set of embryonic lethal mutations that do not produce cuticle. We have cloned six of these genes and found that five code for P450 type enzymes. In arthropods, ecdysteroids are synthesized from dietary cholesterol or phytosteroids via a series of hydroxylation steps catalyzed by P450-type enzymes. In collaboration with Lawrence Gilbert’s laboratory at the University of North Carolina, we have determined that mutations in these P450s all result in low embryonic titers of 20E or its immediate precursor, ecdysone. For four of these enzymes we have identified the exact biochemical step at which they act. Our long-range plans include a study of the transcriptional and translational regulation of these genes with a particular emphasis on uncovering the neuroendocrine signaling pathway that triggers ecdysone biosynthesis. These studies should enable us to learn more about how key cellular and morphological changes are programmed to occur at appropriate times during development. In addition, since all insects require ecdysteroids for normal development, these studies may provide targets for the development of novel agents to control insect populations that have both agricultural and biomedical impact.

 

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Two developmental timing nerons (green) secrete the neropeptide PTTH (green dots) to the endocrine organ (red) of Drosophila to control steroid hormone release.
(M. O'Connor)