Researchers discover a genetic switch controlling the fruit fly's maturation from a slug-like larva to a mobile, sexually active fly.

Working with fruit flies, researchers have discovered a genetic switch that appears to control an array of intricate processes required for the fly to mature from a slug-like larva to a mobile, sexually active fly. The researchers said their discovery in the fly Drosophila could provide insights into how sexual maturation occurs in higher animals, including humans. The researchers, led by Carl S. Thummel, a Howard Hughes Medical Institute investigator at the University of Utah School of Medicine, published their findings in the June 3, 2005, issue of the journal Cell . Thummel and Utah colleagues Kirst King-Jones and Geanette Lam, collaborated on the study with co-author Jean-Philippe Charles from the University of Bourgogne in France. The genetic maturation switch identified by the researchers, called DHR4 , is a member of a family of genes that encode proteins called nuclear receptors. These receptors, triggered by hormones, each control a large number of other genes, giving them a critical role in coordinating complex body processes. Thummel and his colleagues began studying DHR4 because of its pattern of activity in the developing fly and other insects. “Virtually nothing was known about DHR4 , but we found it intriguing because it is expressed transiently during the very early stage of metamorphosis,” he said. DHR4 was also intriguing to the scientists because the gene produces a so-called “orphan” nuclear receptor, whose activating hormone was unknown. To discern the function of DHR4 , the researchers knocked out the gene in two different ways. Co-author Charles created a mutant form of the fly that completely lacked a functioning gene. And Thummel and his colleagues used a technique called RNA interference that allowed them to selectively inactivate the DHR4 gene at different stages of the fly's growth. By analyzing the effects of these two types of gene inactivation, the researchers teased apart two distinct roles of DHR4 in maturation. They found that one effect of DHR4 loss was that larvae of the mutant flies stopped eating too early in development, initiating behaviors that led to early pupa formation. These pupae developed into smaller, lighter adult flies. “These mutants eat and grow normally until their last larval stage,” said Thummel, “when they stop eating prematurely and go into metamorphosis earlier than they should.” The researchers also found that DHR4 -deficient flies showed defects in the process of metamorphosis itself. These defects involved the developmental “circuitry” controlled by the key insect steroid hormone ecdysone, known to be a major orchestrator of biological processes throughout a fly's development and a critical regulator of metamorphosis. “The discovery of DHR4 's role in repressing the genetic cascade triggered by ecdysone was very gratifying, because it filled in a piece of an important puzzle,” said Thummel. “In flies, the work of many laboratories has produced an elegant, detailed model of the developmental machinery triggered by ecdysone. However, there has been one piece missing, which we have been seeking for many years - how the earliest response to ecdysone is repressed. “These genes switch on and off really fast,” explained Thummel. “We knew that ecdysone turns them on, but we never knew what turned them off. Now we know that DHR4 is one of the critical components required for shutting down that response, so proper development can proceed.” According to Thummel, understanding the machinery of maturation in fruit flies could lead to important insights into how the process works in higher animals, including humans. “Everyone knows that steroid hormones are required for puberty and adolescence in humans,” he said. “But we really don't have a good understanding of the targets of the hormone receptors and how they control the myriad changes that comprise sexual maturation in humans. Part of our goal in studying maturation in Drosophila is to use a simple model organism to tackle the major questions of how maturation is regulated and timed. “As we've studied the details of other signaling pathways in Drosophila , we've found they've given us direct clues to what is going on in vertebrate organisms, including humans. So too, we hope that studying these steroid signaling pathways in fly maturation will give us clues as to how steroids control human maturation.” Further studies in his laboratory will concentrate on understanding the molecular trigger for DHR4 , said Thummel. Also, he said, the researchers will seek to map the regulatory pathways DHR4 controls and the tissues within which those pathways function. “This paper provides only a first bare-bones clue to this important process of the timing of maturation,” said Thummel. “Now we want to flesh out this story, to discover the molecular circuitry underlying this critical step in the life cycle.”

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