age-1 is required for non dauer development and normal senescence. Absence of both maternal and zygotic
age-1 confers a dauer constitutive phenotype while animals lacking only zygotic
age-1 live twice as long as wildtype.
age-1 functions at the same point in the dauer genetic epistasis pathway as
daf-2.
daf-2 mutants have a similar phenotype to
age-1 mutants; lack of zygotic
daf-2 confers a dauer constitutive phenotype and a long lifespan. Both
age-1 and
daf-2 are completely suppressed by
daf-16 for both the dauer formation and longevity phenotypes.
age-1 encodes a homolog of the
p110 catalytic subunit of phospatidylinositol 3-kinase (Morris et al., Nature 382, p. 536),
daf-2 encodes an insulin receptor homolog (Kimura et al. abstract), and
daf-16 may encode a fork head transcription factor homolog (Ogg et al. abstract). In order to isolate genes which could be direct targets of PI 3-kinase and insulin receptor signaling, we screened for suppressors of the
age-1(
mg44) dauer constitutive phenotype. Although
daf-2 suppression screens have been saturated (and have yielded only alleles of
daf-16), a screen for suppressors of
age-1 had never been done. We screened a total of 3400 genomes for either zygotic or maternal effect suppressors of
age-1. We isolated 10 independent mutations. Two mutations are alleles of
daf-16. Of the remaining 8 mutations, only 2 (
mg142 and
mg144) suppress multiple alleles of
age-1. One mutation,
mg142, is semi-dominant and maps to the left arm of LGX. It is not yet clear whether
mg142 is a zygotic or maternal effect suppressor. Another mutation,
mg144, is completely dominant, is not a strict maternal effect suppressor, and maps to LGV. Interestingly, neither
mg142 nor
mg144 is able to suppress the dauer constitutive phenotype of
daf-2. It is known from mammalian systems that the insulin receptor activates PI 3-kinase and other signaling molecules such as ras. The fact that
mg142 and
mg144 suppress
age-1 but not
daf-2 implies that there is another output from DAF-2 other than AGE-1 in C. elegans. Experiments in progress include finer mapping of
mg142 and
mg144 and phenotypic and genetic characterization of these alleles. In addition, the screen for suppressors of the
age-1 dauer constitutive phenotype is ongoing.