Heterochronic genes record developmental age in the various tissues and select stage-appropriate programs for nematode life stages L1 through adult. Dauer pathway genes mediate commitment to reproductive growth or the L3 dauer diapause in response to environmental stimuli.
daf-12 acts at the convergence of these pathways, regulating both developmental age and dauer diapause at larval stage L3. Mutants repeat L2 programs at L3 and later stages, and inappropriately choose between reproductive growth and dauer arrest irrespective of environmental conditions. In the adult,
daf-12 mutants also enhance lifespan extension of
daf-2 mutants from 2 fold to 4 fold (Larsen et al, 1995).
daf-12 encodes a nuclear receptor most closely related to the drosophila DHR96 and vertebrate Vitamin D receptors.
daf-12 , two related nematode receptors, and DHR96 define an ancient branch of the nuclear receptor family, sharing a conserved DNA recognition helix.
daf-12 alleles fall into 6 classes based on dauer and heterochronic phenotypes. Molecular lesions within a class strikingly cluster in modular domains of the protein, with several implications for receptor function.
daf-12 gives rise to 3 isoforms expressed throughout development. We suggest that
daf-12 functional complexity can be explained by at least two activities, a and b required for commitment to reproductive growth and the dauer diapause respectively. The molecular identity of
daf-12 as a nuclear receptor suggests a hormonal mechanism in regulatory circuits that record developmental age and control dauer diapause. Interactions with
daf-2 suggest that adult longevity might also be influenced by heterochronic factors.