The dauer larva is a developmentally arrested, non-aging alternate third larval stage formed in response to a low ratio of food to pheromone in the environment. Our lab has previously described the cloning of genes involved in the regulation of this developmental decision. Three of these genes encode components of a protein growth factor regulated signalling pathway:
daf-7 = a novel TGF-B-like ligand,
daf-1= a
type-1 TGF-B-like receptor (Georgi et al., Cell 61: 635), and
daf-4 = a
type-2 BMP/dpp-like receptor (Estevez, M. et al., Nature 365: 644). Mutations in any one of these three genes results in constitutive dauer larva formation (Daf-c). Additional phenotypes associated with mutations in the
daf-4 gene are small adult body size (Sma) and male tail defects (Mab). Mutations in the
daf-8 gene are also Daf-c, and all four genes have been placed at the same step the genetic pathway. Three transposon-insertion alleles of
daf-8 were generated. A region flanking the transposon insertion site was cloned and used to confirm the genomic position of the fragment in the
daf-8 region. Overlapping cosmids in this area were restriction mapped and the areas corresponding to the transposon flanking sequence cloned. Approximately 3 kb of genomic sequence has been determined and the largest open reading frame encodes a MAD/Dwarfin/DPC4 homolog. The Drosophila MAD gene was identified in a genetic screen for enhancers of dpp (Raferty et al., Genetics 139: 241) and is believed to be a downstream effector for dpp signalling (Sekelsky et al., Genetics 139: 1347). The human gene, DPC4 encodes another family member (Hahn et al., Science 271: 350). This indicates a role for these novel proteins as tumor suppressors, since DPC4 is frequently inactivated in pancreatic carcinomas. Three C. elegans genes
sma-2, -3, and -4 encode the Dwarfin protein family (Savage et al., PNAS in press ). Mutants in these genes are Sma and Mab, but not Daf-c. The
daf-8 mutants are Daf-c, but not Sma or Mab. Since the sma and
daf-8 mutants all exhibit aspects of the
daf-4 phenotype, it is possible that these proteins all act downstream of the
daf-4 receptor, but at different developmental times and/or in completely different cells. Preliminary northern blot analysis indicates that
daf-8 is expressed throughout development.