Insulin and insulin-like growth factors (IGFs) signal through a highly conserved pathway and control growth and metabolism in both vertebrates and invertebrates. The well-studied mammalian IGF binding proteins (IGFBPs) do not, however, have obvious sequence homologs in the fruit fly Drosophila. The discovery of a functional ortholog transforms Drosophila into a powerful model system in which to explore metabolic regulation and presents a significant advance in our understanding of the mechanisms by which the actions of insulin-like peptides are regulated.

A research team led by Ernst Hafen from the Institute of Molecular Systems Biology at the ETH in Z rich, Switzerland, employed a genetic strategy to search for negative insulin/insulin-like growth factor signaling (IIS) regulators in Drosophila. The team identified a new functional insulin-binding protein that acts as an IIS antagonist. Dubbed imaginal morphogenesis protein-late 2 (Imp-L2), the new antagonist binds the Drosophila insulin-like peptide 2 (Dilp2), inhibiting its growth-promoting function. Imp-L2 not only has a role in growth regulation - it is also essential for the dampening of insulin signaling under adverse conditions.

The authors hope that better understanding of Imp-L2's role in growth control and insulin signaling in Drosophila will ultimately impact on our understanding of the human ortholog IGFBP-7. This has a regulatory role in pathways that impact upon diabetes and cancer. IGFBP-7 acts as a tumor suppressor in a variety of human organs and differs in the C-terminus from the other IGFBPs.

"Since Imp-L2 and the human tumor suppressor IGFBP-7 display sequence homology in their C-terminal immunoglobulin-like domains, we suggest that their common precursor represents an ancestral insulin-binding protein," says Hafen

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In addition to demonstrating the power of reprogramming, this work offers the promise of powerful new mouse models for autoimmune diseases such as multiple sclerosis and type 1 diabetes, in which the body attacks certain types of its own cells. For example, mature B or T cells specific for nerve cells called glia could be reprogrammed to IPS cells and then used to create mice with an entire immune system that is primed to only attack the glia cells, thereby creating a mouse model for studying multiple sclerosis.

Eventually, researchers will be able to study diseases by following a similar process with human cells, predicts Jaenisch, who is also a professor of biology at Massachusetts Institute of Technology. In principle, this will allow you to transfer a complex genetic human disease into a Petri dish, and study it, he says. That could be the first step to analyze the disease and to define a therapy.

This research was supported by the National Institutes of Health and the Helen Hay Whitney Foundation.

Nicole Giese.

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