Review
Genetic analysis of insulin signaling in Drosophila

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Abstract

Studies in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans have revealed that components of the insulin signaling pathway have been highly conserved during evolution. Genetic analysis in Drosophila suggests that structural conservation also extends to the functional level. Flies carrying mutations that reduce insulin signaling have a growth deficiency phenotype similar to that seen in mice with disruptions of genes encoding insulin-like growth factors (IGFs) or the IGF-I receptor. Recent studies in flies have demonstrated a role for the insulin signaling pathway in the regulation of metabolism, reproduction and lifespan via modulation of central neuroendocrine pathways. Similarly, mice with loss of brain insulin receptors or insulin receptor substrate 2 deficiency exhibit neuroendocrine defects and female infertility. These parallels suggest that the insulin system has multiple conserved roles, acting directly to modulate growth and indirectly, via the neuroendocrine system, to modulate peripheral physiology in response to changes in nutrient availability.

Section snippets

The Drosophila insulin receptor

Determination of the complete structure of Inr (see Glossary) 7., 8., confirmed the results of biochemical studies suggesting that the Drosophila receptor, like its mammalian counterparts, comprised two α and two β subunits, with a cytoplasmic tyrosine kinase in its β subunit that was activated upon insulin binding [9]. The degree of sequence conservation between the fly and human receptors in some domains, especially the kinase domain, is remarkable, given the evolutionary distance between

Insulin-like peptides in Drosophila

The ability of INR to bind mammalian insulin suggests that insulin-like ligands should be present in Drosophila. Accordingly, a new family of genes was recently identified that encodes seven Drosophila insulin-like peptides [16] (dilp1–5). The deduced amino acid sequences predict a signal peptide, a B chain, a C peptide and an A chain. The presence of consensus proteolytic processing sites suggests that the mature peptides are composed of A and B chains and lack the C peptide, as in mammalian

Insulin signaling and growth control

The most obvious role of insulin signaling uncovered by genetic analysis in Drosophila is in the regulation of growth and body size. The ability to generate visible aberrant phenotypes by perturbation of cellular growth has allowed studies of growth regulation to progress rapidly. However, strong InR mutations are recessive embryonic lethal 8., 22., indicating an essential function for InR during normal development beyond growth control. This is consistent with the position of InR as the first

Insulin signaling and metabolism, reproduction and lifespan

Recent data also implicate INR signaling in metabolic regulation in flies. The first genetic evidence that insulin signaling impacted on metabolism in lower organisms came from daf-2 mutations in C. elegans. Worms with decreased DAF-2 function have greater lipid stores than their wild-type counterparts [46]. Similarly, dwarf flies with mutations in chico [15] and InR 4., 16. exhibit up to a fivefold increase in stored triglyceride. Because insulin receptor activation stimulates lipogenesis in

Conclusions

Molecular and genetic analysis of the insulin signaling pathway in Drosophila has revealed striking conservation at both the structural and functional levels. Recent studies emphasize the central role of insulin in the coordinated regulation of growth, metabolism, reproduction and lifespan. These data suggest that the level of activity of the insulin pathway reflects environmental conditions, in particular, nutrient availability, and serves to adapt many aspects of physiology for optimum

Glossary

Age-1
Caenorhabditis elegans homolog of PI3K
CHICO
Drosophila homolog of IRS
daf-2
gene encoding Caenorhabditis elegans insulin receptor homolog
Dakt
gene encoding Drosophila homolog of PKB/Akt
dilp1–7
Drosophila insulin-like peptide genes 1–7
Dp110
gene encoding Drosophila homolog of the catalytic subunit of PI3K
Dstpk61
Drosophila homolog of PDK-1
FKHR
Forkhead-related transcription factor
GAP
GTPase-activating protein.
GSK-3
Glycogen synthase kinase-3
IGF
Insulin-like growth factor
InR
Insulin receptor gene in

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