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The Drosophila insulin receptor and insulin signaling
The Drosophila insulin receptor and insulin signaling.
Drosophila insulin receptor regulates axon guidance in the developing visual system. Insulin receptors are abundantly expressed in the central nervous system of invertebrates and vertebrates, although their roles have remained elusive. We have discovered a novel function for the Drosophila insulin receptor (DInR) in axon guidance in the visual system. We have shown that DInR function is necessary for photoreceptor cell (R cell) axon targeting from the retina to the brain to form a precise retinotopic map during development. DInR functions as a guidance receptor for the Dock pathway: DInR interacts directly with Dock, to link extracellular signals to axonal migration via activation of the downstream effector p21-activated kinase, Pak. This function of DInR is genetically independent of Chico, the Drosophila IRS homolog. Based upon this, we proposed that DInR signals independently through Dock and Chico to control axon guidance and growth, respectively (Song et al., 2003), reviewed in a comment accompanying our Science article, (Dickson, 2003). To test this model, we have generated a set of transgenic Drosophila that express DInR proteins with mutations in potential Dock or Chico binding sites in the signaling portion of DInR. If our model is correct, expression of DInR proteins with mutations in Dock-binding sites should rescue dinr-associated growth defects but not axon guidance and expression of DInR proteins with mutations in Chico-binding sites should not axon guidance but not growth. If successful, the growth-rescued dinr mutants will provide a clean background for more detailed studies of the role of DInR in axon guidance. This battery of DInR proteins carrying mutations in signaling protein-binding sites will also be useful for our physiological experiments, to define DInR-mediated signaling pathways responsible for sugar and fat metabolism in insects (see next section).
Figure 7. Df[dilp1-5] flies are small and ‘diabetic.’ A. Photos of adult females show that Df[dilp1-5] animals (right) are homozygous viable but smaller than wild type (left). B. Circulating sugar levels (trehalose + glucose; glucose comprises < 2% of total sugar) are elevated in Df[dilp1-5] animals compared to wild type (w1118) or parental (d02567) controls at early and late third instar larval stages. Levels are even higher when Insulin Producing Cells are ablated, as shown previously (Rulifson et al., 2002). Sugar levels are restored to normal by expression of DILP2 (rescue).
(Zhang et al., 2009). Insulin/Insulin-like growth factor signaling regulates homeostasis and growth in mammals, and is implicated in diseases from diabetes to obesity to cancer. In Drosophila melanogaster, as in other invertebrates, multiple Insulin-Like Peptides (DILPs) are encoded by a family of related genes. We used genetic approaches to ask whether these DILPs play roles in insect physiology that are similar to the roles of insulin and insulin-like growth factor in mammals. In a recent study, that is, to our knowledge, the first report of genetic loss-of-function mutations in insect insulin-like peptide genes, we generated small deficiencies that uncover single or multiple dilps. Deletion of dilps1-5 generated homozygotes that are small and severely growth-delayed, indicative of a role for these DILPs in growth, which is consistent with studies from other groups and with the finding that DInR is required for growth. Surprisingly, the Df[dilp1-5] animals were viable and fertile, providing us with a true-breeding stock to carry out physiological studies. These animals display reduced overall metabolic activity and are sluggish. They also display decreased whole body triglyceride levels and prematurely activate autophagy, indicative of 'starvation in the midst of plenty,' a hallmark of Type I diabetes. Furthermore, circulating sugar levels are elevated in Df [dilp1-5] homozygotes during eating and fasting. Thus these Df[dilp1-5] animals display many of the manifestations of human Type I diabetes, but, in contrast to the situation for mammals, where lack of insulin is lethal if untreated, these flies are viable. Experiments are underway to examine similarities and differences between mammals and insects that may explain the mammalian-like changes in fat and sugar metabolism seen in the mutants as well as the unexpected survival of these lean, ‘diabetic’ flies. At the same time, the set of mutants in DInR signaling motifs described above will allow us to define the signaling pathways regulating sugar and fat metabolism and, in the long term, to model abnormalities in insulin-responsiveness that lead to insulin resistance and Type 2 diabetes.