daf-2;ins-18

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Genetic mutants with daf-2, ins-18 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Diet
NGM
Lifespan (days)
28.0
Lifespan change (compared to wild type)
75.00%
Phenotype
The mean life span of ins-18;daf-2 double mutants was shortened by 7.0 days at 20 °C compared with daf-2 animals. These data indicate that INS-18 is required for longevity of daf-2 animals.
Lifespan comparisons
Double mutant daf-2(e1370);ins-18(tm339) has a lifespan of 28.0 days, while single mutant daf-2(e1370) has a lifespan of 42.33 days, single mutant ins-18(tm339) has a lifespan of 18.0 days and wild type has a lifespan of 16.0 days.
Type of interaction
See methods
Dependent
Citation
View abstract
Matsunaga Y et al., 2012, Physiological function, expression pattern, and transcriptional regulation of a Caenorhabditis elegans insulin-like peptide, INS-18. Biochem Biophys Res Commun. 423(3):478-83 22683638 Click here to select all mutants from this PubMed ID in the graph
Abstract
In Caenorhabditis elegans, insulin/insulin-like growth factor (IGF)-1 signaling (IIS) is an important pathway that controls larval diapause and adult lifespan. The IIS pathway is modulated by many insulin-like peptides (ILPs) through the DAF-2 receptor, the sole insulin/IGF-1 receptor-like protein in C. elegans. We previously identified the ILP, INS-18, and predicted its tertiary structure to be similar to the crystal structures of human insulin and IGF-1. In this study, the physiological function of INS-18 was first examined by gene disruption and overexpression, and we identified INS-18 as a DAF-2 antagonist required for larval diapause and longevity. Analysis of the INS-18 expression pattern using a reporter gene showed it to be expressed in nerve cells, including hermaphrodite-specific neurons (HSNs) at the adult stage. Other ILP expressions have not been previously observed in HSNs, and we believe that INS-18 expression in these cells may contribute to longevity by regulating reproduction. Loss of the DAF-16 transcription factor located downstream of the IIS pathway completely blocked ins-18 expression. We propose a positive feedback model for the regulation of ins-18 expression in which an antagonist binding to the DAF-2 receptor increases ins-18 gene expression, thus leading to increased INS-18 protein levels and increased DAF-2 receptor binding. Thus, this study provides a new insight into the hormonal regulation of insulin, an important and widespread process in the animal kingdom.

Temperature °C
25
Diet
NGM
Lifespan (days)
31.6
Lifespan change (compared to wild type)
216.00%
Phenotype
daf-2 and double mutant animals had the same lifespan at 25 °C, indicating that INS-18 does not affect longevity in the absence of DAF-2 activity.
Lifespan comparisons
Double mutant daf-2(e1370);ins-18(tm339) has a lifespan of 31.6 days, while single mutant daf-2(e1370) has a lifespan of 31.6 days, single mutant ins-18(tm339) has a lifespan of 10.0 days and wild type has a lifespan of 10.0 days.
Type of interaction
See methods
Additive (positive)
Citation
View abstract
Matsunaga Y et al., 2012, Physiological function, expression pattern, and transcriptional regulation of a Caenorhabditis elegans insulin-like peptide, INS-18. Biochem Biophys Res Commun. 423(3):478-83 22683638 Click here to select all mutants from this PubMed ID in the graph
Abstract
In Caenorhabditis elegans, insulin/insulin-like growth factor (IGF)-1 signaling (IIS) is an important pathway that controls larval diapause and adult lifespan. The IIS pathway is modulated by many insulin-like peptides (ILPs) through the DAF-2 receptor, the sole insulin/IGF-1 receptor-like protein in C. elegans. We previously identified the ILP, INS-18, and predicted its tertiary structure to be similar to the crystal structures of human insulin and IGF-1. In this study, the physiological function of INS-18 was first examined by gene disruption and overexpression, and we identified INS-18 as a DAF-2 antagonist required for larval diapause and longevity. Analysis of the INS-18 expression pattern using a reporter gene showed it to be expressed in nerve cells, including hermaphrodite-specific neurons (HSNs) at the adult stage. Other ILP expressions have not been previously observed in HSNs, and we believe that INS-18 expression in these cells may contribute to longevity by regulating reproduction. Loss of the DAF-16 transcription factor located downstream of the IIS pathway completely blocked ins-18 expression. We propose a positive feedback model for the regulation of ins-18 expression in which an antagonist binding to the DAF-2 receptor increases ins-18 gene expression, thus leading to increased INS-18 protein levels and increased DAF-2 receptor binding. Thus, this study provides a new insight into the hormonal regulation of insulin, an important and widespread process in the animal kingdom.

Search genes: daf-2 ins-18

Entrez ID
Symbol
GenAge
Wormbase ID

175410
daf-2
View on GenAge (daf-2)
WBGene00000898

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.

Entrez ID
Symbol
GenAge
Wormbase ID

172600
ins-18
View on GenAge (ins-18)
WBGene00002101

INSulin related

Locus: CELE_T28B8.2

Wormbase description: ins-18 encodes one of 40 C. elegans insulin/IGF-like peptides; INS-18, along with INS-1, are the only two C. elegans insulins that contain a C peptide, characteristic of mammalian insulins, connecting the B and A chains; overexpression of ins-18 induces dauer arrest at 26 degrees C and enhances the dauer arrest seen in a daf-2 mutant at 20 degrees C, suggesting that INS-18 functions to antagonize DAF-2 receptor signaling; in addition, daf-7; ins-18 doubly mutant animals show dauer maintenance defects, suggesting that INS-18 activity is required to properly maintain the dauer developmental state; ins-18::gfp reporters are expressed in neurons and the intestine.

Orthologs of daf-2;ins-18 in SynergyAge

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Species	Gene

Not in SynergyAge
Species	Gene

Orthologs of daf-2 in SynergyAge

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Species	Gene
Drosophila melanogaster	InR

Not in SynergyAge
Species	Gene
Mus musculus	Insr
Mus musculus	Igf1r
Mus musculus	Insrr

Orthologs of ins-18 in SynergyAge

Show in SynergyAge
Species	Gene