Worm Breeder's Gazette 14(3): 35 (June 1, 1996)
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
Waksman Institute, Rutgers University, Piscataway, NJ 08855
Previous work examining the transduction of TGF-B superfamily signal at the level of the membrane has resulted in the formulation of a general model by which this may occur. Transmembrane receptors which interact specifically with TGF-B superfamily ligands have been isolated and have been demonstrated to be required for proper transduction in several organisms. A subset of these receptors contain a serine-threonine kinase domain, and can be categorized into two classes, type I and type II, which differ considerably with each other in their non-kinase regions. It is thought that the mature protease-cleaved dimeric ligand interacts with appropriate type II receptors followed by the formation of an oligomeric complex with specified type I receptors. This complex then conceivably transduces the appropriate signal to downstream molecules, eventually resulting in intracellular changes and/or altered expression patterns of specific gene targets. In the worm, the dauer and small pathways are examples of mechanisms controlled by TGF-B like ligands. In the dauering pathway, the products of daf-l, daf-4 are receptors and serve to transduce the signal. Additionally, the dwarfins comprise a group of genes which encode products that have been implicated in the TGF-B transduction pathway in the nematode (Savage et al., PNAS 1996; Savage et al., WBG 1995) and in Drosophila (Sekelsky et al., Genetics 139: 1347-1358, 1995) . In the worm, the sma-2, sma-3, and sma-4 genes are dwarfins that have been characterized by our group. The mutant phenotypes of these genes are a subset of those exhibited by daf-4. However, the sma phenotypes are not observed in other dauer mutants. Thus, daf-4 intersects the dauering and small pathways. Since daf-l does not exhibit the small phenotype, we hypothesized that there should be another type I receptor transducing a TGF-B-like signal to the sma gene products, that when mutated, results in small animals. Using molecular tools, we had identified tre-1 as a novel type I receptor in C. elegans. tre-1 demonstrates a large degree of homology with other type I receptors, particularly the thickveins gene in Drosophila. Searches of extant mutations in the region of tre-1 indicated that sma-6 was nearby. Given that four genes mutate to a small phenotype, other genes in the pathway may also yield the same phenotype. Based on these data, the possibility was raised that sma-6 may encode tre-1. Germline transformation experiments confirmed this hypothesis, whereby a 9kb genomic fragment containing the tre-1 gene and flanking regions extending into, but not encompassing, adjacent predicted transcripts was sufficient to rescue sma-6 mutants and revert F1 transformed progeny to wild-type length. We are currently continuing to characterize the expression of tre-1 and analyze interactions with other components of the small pathway. In addition, we have isolated superfamily ligands in the worm, including tig-1, tig-2, and tig-3 (Krishna, WBG, 1995). We are seeking mutations in the respective regions, and we are continuing to characterize these genes. These results help us to define the specificity of TGF-B signaling by demonstrating that different type I receptors are able to elicit varying biological responses. Furthermore, we have completed a large genetic screen in order to identify other mutations that yield small animals. Our results with sma-6 validate this screen, and we hope to isolate other novel components of the pathway. Based on these results, we are also examining sma-5 and sma-8 for potential participation in the signaling pathway.