THE DAF-3 SMAD PROTEIN ANTAGONIZES TGF-BETA-RELATED RECEPTOR SIGNALING IN THE CAENORHABDITIS-ELEGANS DAUER PATHWAY

Signals from TGF-beta superfamily receptors are transduced to the nucl eus by Smad proteins, which transcriptionally activate target genes. I n Caenorhabditis elegans, defects in a TGF-beta-related pathway cause a reversible developmental arrest and metabolic shift at the dauer lar val stage. Null mutations in daf-3 suppress mutations in genes encodin g this TGF-beta signal, its receptors, and associated Smad signal tran sduction proteins. daf-3 encodes a Smad protein that is most closely r elated to mammalian DPC4, and is expressed throughout development in m any of the tissues that are remodeled during dauer development. DAF-4, the type II TGF-beta receptor in this pathway, is also expressed in r emodeled tissues. These data suggest that the DAF-7 signal from sensor y neurons acts as a neuroendocrine signal throughout the body to direc tly regulate developmental and metabolic shifts in tissues that are re modeled during dauer formation. A full-length functional DAF-3/GFP fus ion protein is predominantly cytoplasmic, and this localization is ind ependent of activity of the upstream TGF-beta-related pathway. However , this fusion protein is associated with chromosomes in mitotic cells, suggesting that DAF-3 binds DNA directly or indirectly. DAF-3 transge nes also interfere with dauer formation, perhaps attributable to a dos age effect. A truncated DAF-3/GFP fusion protein that is predominantly nuclear interferes with dauer formation, implying a role for DAF-3 in the nucleus. These data suggest that DAF-7 signal transduction antago nizes or modifies DAF-3 Smad activity in the nucleus to induce reprodu ctive development; when DAF-7 signals are disabled, unmodified DAF-3 S mad activity mediates dauer arrest and its associated metabolic shift. Therefore, daf-3 is unique in that it is antagonized, rather than act ivated, by a TGF-beta pathway.