In many organisms, growth occurs primarily during early juvenile phases. When a specific body size is reached, the organism stops growing and transitions to a sexually mature adult (at puberty in mammals and at metamorphosis in insects). Nevertheless, it is unclear how organisms sense when they are large enough for this transition. In the fruitfly, Drosophila, metamorphosis is triggered by the steroid hormone ecdysone, synthesized in an endocrine tissue called the prothoracic gland (PG). One key activator of ecdysone synthesis is the protein hormone, PTTH. Elimination of PTTH delays ecdysone synthesis and causes large and developmentally delayed adults to form. The cellular "machinery" within the PG by which PTTH triggers ecdysone synthesis has not been identified, and yet this identification is critical to understanding how the timing of metamorphosis, and hence final body size, is regulated. This research project will test the hypothesis that PTTH activates ecdysone synthesis via a regulatory pathway (MAP kinase pathway) in the PG. Transgenes inhibiting or activating the MAP kinase pathway will be expressed specifically in the PG to determine if these transgenes either block the ability of PTTH to induce ecdysone synthesis, or activate ecdysone synthesis in the absence of PTTH. In addition, transgenes will be used to increase or decrease PTTH synthesis, and the effects of changes in PTTH levels on MAP kinase activity will be determined. Successful completion of these experiments will provide essential information on the machinery used by organisms to control the timing of developmental transitions and hence final body size. In addition, this project will support the development of the next generation of scientists by training undergraduate and graduate researchers in genetic and molecular techniques.
In many organisms, including mammals and insects such as the fruit fly Drosophila melanogaster, growth occurs during an early, sexually immature juvenile phase. Then, at a particular time, the organism transitions to a nongrowing, sexually mature, adult in a process that in mammals is called puberty and in insects is called metamorphosis. The decision of when to undergo this transition to adulthood is critical for any organism because this decision not only specifies final adult body size but also the reproductive rate – the number of generations possible within a given time. Although the timing of the transition to adulthood is controlled mainly by genetic factors, environmental factors also play a role in this timing. In particular, nutrient availability tends to advance the onset of this transition in both mammals and Drosophila, whereas nutrient deprivation tends to delay this transition. However, the link at the molecular and cellular level between nutrient availability and this timing remained unclear. During the course of this award, we examined this question using the fruit fly Drosophila melanogaster as our system. Initially we discovered that increasing insulin growth factor signaling in Drosophila larvae not only increased growth rate, as expected, but also advanced the onset of metamorphosis by increasing expression of genes synthesizing the molting and metamorphosis hormone ecdysone. This observation suggested that insulin signaling might mediate the effects of nutrition on the timing of metamorphosis. Then we examined the mechanism linking insulin signaling and expression of ecdysone biosynthetic genes. We found that expression of the BTB transcription factor "broad", which was previously shown to be required for metamorphosis, was blocked in larvae with deficient insulin signaling. This observation suggests that broad expression links insulin signaling with onset of metamorphosis in Drosophila. Finally, we identified several putative intermediates linking insulin with broad expression. The results that we obtained from this award have identified the underlying mechanism linking insulin with the transition to adulthood in Drosophila. Given the similarities by which mammals, including humans, decide when to transition to adulthood, these studies might have broad significance. For example, there is currently an epidemic of children reaching puberty at extremely young ages, which causes a number of physical and psychological problems. However, the underlying cause is unknown. Therefore, our studies might also have broad medical interest. During the course of the award we also participated in educational and outreach activities with the objective and bringing younger and underrepresented individuals into the research career track. We hosted several high school students who performed summer research projects with us. We also participate avidly in our departmental Bioc 115 program, in which Rice freshmen gather in groups to study specific papers that have been recently published by Rice Biochemistry department labs. The course includes lab tours and informal meetings between the undergraduates and lab researchers. This course is instrumental in attracting undergraduates at a young age to Biochemistry department research labs.
