ddr-2;pha-4

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Genetic mutants with ddr-2, pha-4 alterations

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

Temperature °C
20
Lifespan (days)
17.68
Lifespan change (compared to wild type)
7.22%
Phenotype
pha-4 is not required for eIF4H/drr-2 inhibition to extend lifespan, as the RNAi of eIF4H/drr-2 extends lifespan to a similar extent in the pha-4(zu225) mutant background compared to that in wild types.
Lifespan comparisons
Double mutant ddr-2(RNAi);pha-4(zu225) has a lifespan of 17.68 days, while single mutant ddr-2(RNAi) has a lifespan of 20.43 days, single mutant pha-4(zu225) has a lifespan of 14.7 days and wild type has a lifespan of 16.49 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Ching TT et al., 2010, drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell. 9(4):545-57 20456299 Click here to select all mutants from this PubMed ID in the graph
Abstract
Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2, a DR-responsive gene recently identified, in determining the longevity of Caenorhabditis elegans. Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient-sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans. Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.

Temperature °C
20
Lifespan (days)
19.2
Lifespan change (compared to wild type)
36.75%
Phenotype
pha-4 is not required for eIF4H/drr-2 inhibition to extend lifespan, as the RNAi of eIF4H/drr-2 extends lifespan to a similar extent in the pha-4(zu225) mutant background compared to that in wild types.
Lifespan comparisons
Double mutant ddr-2(RNAi);pha-4(zu225) has a lifespan of 19.2 days, while single mutant ddr-2(RNAi) has a lifespan of 17.34 days, single mutant pha-4(zu225) has a lifespan of 16.58 days and wild type has a lifespan of 14.04 days.
Type of interaction
See methods
Almost additive (positive)
Citation
View abstract
Ching TT et al., 2010, drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell. 9(4):545-57 20456299 Click here to select all mutants from this PubMed ID in the graph
Abstract
Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2, a DR-responsive gene recently identified, in determining the longevity of Caenorhabditis elegans. Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient-sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans. Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.

Search genes: ddr-2 pha-4

Entrez ID
Symbol
GenAge
Wormbase ID

180622
ddr-2
View on GenAge (ddr-2)
WBGene00017381

Discoidin domain-containing receptor tyrosine kinase B

Locus: CELE_F11D5.3

Wormbase description: F11D5.3 encodes a putative tyrosine kinase homologous to human RS1 (OMIM:312700, mutated in juvenile X-linked retinoschisis).

Entrez ID
Symbol
GenAge
Wormbase ID

180357
pha-4
View on GenAge (pha-4)
WBGene00004013

Defective pharyngeal development protein 4

Locus: CELE_F38A6.1

Wormbase description: pha-4 encodes a FoxA transcription factor; during embryonic development, PHA-4 functions as an organ identity gene whose activity is necessary and sufficient for development of the pharynx/foregut; in addition, PHA-4 plays a key role in regulation of diet-restriction-induced longevity in adult animals; PHA-4 expression begins early in embryogenesis and is seen in pharyngeal and intestinal cells (foregut and midgut); PHA-4 is also expressed later in the developing somatic gonad.

Orthologs of ddr-2;pha-4 in SynergyAge

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Species	Gene

Not in SynergyAge
Species	Gene

Orthologs of ddr-2 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Ddr1
Mus musculus	Ddr2

Orthologs of pha-4 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	FoxK