Worm Breeder's Gazette 15(1): 56 (October 1, 1997)

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.

sup-17 encodes an ADAM protein related to Drosophila kuzbanian

Chenhui Wen1, Mark M. Metzstein2, Iva Greenwald1

1 HHMI/Biochemistry, Columbia University, 701 West 168th Street, Room 720, NY, NY 10032
2 Dept. of Biology, MIT 68-411, Cambridge, MA 02139

        Previous genetic analysis established that sup-17 facilitates
lin-12 signalling (Tax et al., Genetics, in press).  With the
invaluable assistance of the genome project, we have cloned sup-17 and
shown that the predicted SUP-17 protein is a member of the ADAM family
of proteases (see Wolfsberg and White, Devel. Biol. 180, 389-401,
1996); in particular, SUP-17 is very similar to Drosophila kuzbanian
(KUZ), which functions in Drosophila and vertebrate neurogenesis (Rooke
et al., Science 273, 1227-1231, 1996; Pan and Rubin, Cell 90, 271-280,
1997) (see Figure).

        We have extended the genetic studies of Tax et al. (1997) by
showing that sup-17 does not act downstream of lin-12.  Reduction or
elimination of sup-17 activity suppresses the effects of lin-12(d)
mutations (see Tax et al., 1997), an allelic series of hypermorphs that
result from point mutations in the extracellular domain.  In contrast,
we have found that reducing sup-17 activity cannot suppress mutant
phenotypes associated with lin-12(intra).  The lin-12(intra)  transgene
expresses the intact intracellular domain under the control of lin-12
regulatory sequences and behaves like a constitutively active receptor.
It is incompletely penetrant for its effects on the AC/VU decision and
VPC specification, and hence does not elevate lin-12 activity as much
as the stronger lin-12(d) alleles.  Furthermore, we have found that
sup-17 can enhance the AC/VU decision defect of a partial
loss-of-function lin-12 allele, implying that it does not
require a lin-12(d) lesion to influence lin-12 activity.  Since sup-17
can suppress lin-12(d) mutations but cannot suppress lin-12(intra), we
can infer that sup-17 does not act downstream of the activated

        We have also found that the interaction between sup-17!and
lin-12 occurs within the same cell. By using a laser microbeam to
isolate Z1.ppp or a vulval precursor cell from its normal source of
signal, we showed that sup-17 mutations reduce the cell intrinsic level
of constitutive lin-12 activity in lin-12(d) mutants.  This result
suggests that sup-17 acts cell autonomously and that its action is not
dependent on ligand-binding.

        The genetic analysis of the relationship between sup-17 and
lin-12 in C. elegans complements and extends the results from genetic
studies of the relationship between the Drosophila kuz  and Notch genes
(Pan and Rubin, 1997).  SUP-17/KUZ may function in the proteolysis of
LIN-12/NOTCH proteins.  There is evidence for a cleavage event in the
extracellular domain of C. elegans, Drosophila, and human NOTCH
proteins (Christensen et al., Development 122, 1373-1383, 1994;
Blaumueller et al., Cell 90, 281-291, 1997; Pan and Rubin, 1997).
Furthermore,  KUZ is required in vivo for the proteolytic processing of
NOTCH into two fragments consistent with a cleavage event in the
extracellular domain (Pan and Rubin, 1997).  Further work in several
systems will be directed towards understanding how proteolysis
influences LIN-12/Notch activity.

        Special thanks to Frans Tax, Jim Thomas, Chip Ferguson and Bob