Worm Breeder's Gazette 14(2): 40 (February 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.


Cathy Savage, Yi-Ming Wu, Marsha Smith, Richard W. Padgett

Waksman Institute, Rutgers University, Piscataway, NJ 08855

        We are interested in using C. elegans genetics as a tool in
identifying components of TGF-b-like signaling pathways. Our attention
has focused so far on the characterization of sma-2, sma-3, and sma-4,
which function with the TGF-b-like receptor DAF-4 (WM95 p. 56; Savage et
al., PNAS, in press). Mutants for each of these genes have at least two
phenotypes in common: small body size (Sma) and specific male tail ray
and spicule defects (Mab). We have found that sma-2, sma-3, and sma-4
encode related proteins, the dwarfins, that appear to act downstream of
the receptor. Although the dwarfins are novel proteins, the family
includes the Mad gene product in Drosophila, which functions in the dpp 
TGF-b-like pathway (Sekelsky et al., Genetics 139: 1347-1358).
Additional members of the family are being uncovered at an alarming rate
(see abstract by Das et al., this gazette). We are therefore encouraged
by the success of using the phenotypes of the sma genes as criteria for
the identification of TGF-b pathway components.

        To identify other components of this pathway, it seemed
reasonable to continue looking at Small mutants, using as a second
criterion the presence of specific male tail defects. Existing alleles
of the other four sma genes, sma-1, sma-5, sma-6, and sma-8, do not have
the daf-4 Mab phenotype (S. Baird, personal communication). We are
therefore doing an old-fashioned F2 screen to look for additional Sma
mutants. In our first efforts, Sma mutants are being recovered at a rate
of ~1/100 genomes scored; and we are aiming to screen at least 10,000
chromosomes. To characterize these mutations, we will place them in
complementation groups, map any new genes, and determine the male tail
phenotypes. Since we expect to make many new alleles of sma-2, sma-3,
and sma-4, we have decided to screen through the new mutants first by
doing a complementation test with a sma-4sma-3sma-2 triple mutant. This
test will allow us to identify quickly those that are candidates for new
genes. Six new Sma mutants have been analyzed this way: 4/6 are alleles
of sma-2, sma-3, or sma-4. Of the remaining two mutants, one was
X-linked, so that we were able to score for male tail defects
immediately, but no defects were seen (n=20). The next step will be to
make him-5 double mutants with the alleles that remain. We have already
made him-5  doubles with three other new Sma mutants. Since these three
mutants have not yet been tested for complementation with  sma-2, sma-3,
and sma-4, they may include new alleles of these genes. All three
mutants had male tail defects, and one of the three showed the
characteristic fusions of the Mab phenotype of TGF-b pathway components.

        Ultimately, we expect to clone those genes that are likely to be
in this TGF-b-like pathway. The pathway is currently defined only by the
type II receptor, DAF-4, and the three dwarfins, SMA-2, SMA-3, and
SMA-4. In our Small mutant collection we may identify mutations in a
ligand or type I receptor for this pathway. Ongoing efforts to identify
such components molecularly (see abstracts by Krishna et al., this
gazette) may help in fitting together the pieces of this pathway.
Finally, there are likely to be other unidentified components of this
signal transduction pathway, which we hope to identify using this
genetic approach.