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.

TGF-B Superfamily Signaling in C. elegans

Srikant Krishna, Richard W. Padgett

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.