During early larval development the decision between reproductive growth and dauer formation is determined by sensory cues. TGF-beta, insulin-like and cGMP pathways integrate this sensory information, and relay signals throughout the organism by an endocrine mechanism. These inputs converge on the orphan nuclear hormone receptor DAF-12 in cellular targets. To better understand the coupling between these pathways, we investigated the mutant
mig-8(
rh50) , which has
daf-12 -like phenotypes. We isolated more
mig-8 alleles and found two phenotypic classes. Class 1 mutants, which include the
rh50 allele, show delayed migration of the gonadal leader cells. Class 2 mutants arrest as partial dauer larvae, which slowly recover to infertile adults. The Daf-c locus
daf-9 mapped near
mig-8 . By complementation tests, we found that
mig-8 and
daf-9 are the same gene. How do
daf-9 and
daf-12 act together? Epistasis experiments place
daf-9 downstream of TGF-beta and insulin-like signaling and upstream of
daf-12 , showing that
daf-9 couples these inputs to
daf-12 . We cloned
daf-9 and found that it encodes a member of the cytochrome P450 family related to vertebrate steroidogenic and fatty acid hydroxylases. This molecular identity suggests that DAF-9 could synthesize or degrade a DAF-12 ligand. Consistent with this,
daf-9 has phenotypes that resemble
daf-12 mutants with lesions in predicted ligand contact residues.
daf-9 and
daf-12 mutants also have similar effects on ageing, further lengthening the long life of insulin-like receptor mutants
daf-2(
e1370) , and abolishing the longevity of gonad ablated animals. The expression of
daf-9 in sensory neurons, hypodermis, and somatic gonad suggests potential endocrine tissues. We postulate that the DAF-9 substrate/DAF-12 ligand may be a sterol derivative, because cholesterol privation results in phenotypes similar to
daf-9 and
daf-12 mutants. Together these findings provide substantial evidence that lipophilic hormones influence reproductive development and longevity.