Mutants affected in the decision to form dauer larvae are either dauer-constitutive, which form dauer larvae in abundant food, or dauer-defective, which cannot form dauer larvae when starved. Interactions between specific dauer-constitutive and dauer-defective mutants have been used to construct a pathway for gene action.
daf-4 ,a dauer-constitutive gene near the end of the pathway was cloned by transposon tagging. Sequences flanking the transposon insertion site were used to isolate genomic and cDNA clones. Microinjection of one of the genomic clones into the germline of
daf-4 mutants transforms their progeny to wild-type, demonstrating that the cloned DNA conveys
daf-4 function. The cDNA's encode a kinase 33% identical to the kinase domain of the
daf-1 transmembrane receptor kinase (Georgi et al., Cell 61:635, 1990), and 40% identical to the kinase domain of the activin receptor (Matthews and Vale, Cell 65:973, 1991). A
daf-4 hydrophobicity plot suggests it has transmembrane and extracellular domains. It is intriguing that the putative extracellular domains of the
daf-4 and
daf-1 proteins share a short cysteine-rich sequence motif with the activin receptor and the TGF- 1 binding protein. It is possible that the
daf-1 and
daf-4 proteins are C. elegans homologs of the mammalian type I and type II TGF- receptors previously proposed by Laiho et al. (JBC 265:18518,1990). Thus, the pathway of signal transduction that regulates development of the C. elegans dauer larva may be the nematode analogue of a TGF- signalling system. The
daf-12 gene specifies what we believe to be the last step in signal transduction. It encodes a member of the steroid/thyroid hormone receptor superfamily. Its sequence appears to be most similar to the human Vitamin D and Retinoic Acid receptors (Yeh and Riddle, 1991 C. elegans Meeting abstracts, p. 349). Whereas
daf-1 and
daf-4 are required for normal non-dauer development,
daf-12 activity is required for dauer larva morphogenesis. We propose that the activin-receptor-like daf kinases phosphorylate proteins that promote growth, and directly or indirectly inactivate the
daf-12 receptor, possibly by preventing synthesis of a dauer-inducing hormone.