Cell migration is an essential process for organogenesis in animal development. The distal tip cell (DTC; gonadal leader cell) migration of the nematode C. elegans serves as a good model system to study the mechanism of cell migration in organ morphogenesis. The
mig-17 mutants show gonadogenesis defects due to the mis-directed migration of DTCs. The
mig-17 gene encodes a secreted metalloprotease that belongs to the ADAM (A Disintegrin And Metalloprotease) family. The MIG-17 protein is expressed in the body wall muscles and localizes on the surface of the gonad. It is thought that the normal DTC migration is achieved by MIG-17-mediated degradation of ECM molecules in basement membranes. To identify genes functionally interact with
mig-17, suppressors of a
mig-17 null mutant have been isolated.
saf-2 (suppressor of ADAM family defect) is one of the genes defined by suppressors that can bypass the requirement of the MIG-17 activity for DTC migration.
saf-2 mutations,
k193 and
k196, were mapped to the right arm of the chromosome X. Cloning and sequence analysis revealed that
saf-2 alleles have mutations in the
let-2 gene encoding the alpha2 subunit of type IV collagen. Moreover, the GFP-tagged
let-2 constructs carrying
k193 or
k196 mutations suppressed the DTC migration defects of
mig-17 mutants, while the wild-type
let-2::GFP fusion gene did not, indicating that
saf-2 and
let-2 are the same gene. However, two known
let-2 alleles,
g25 and
b246, failed to suppress
mig-17. We speculate that this allele-specificity is due to the differences of mutation sites, because we found the
saf-2 mutations in the region around the C terminal non-collagenous (NC1) domain of the LET-2 protein. In order to examine the effect of the NC1 domain of LET-2 on suppression of
mig-17, the GFP fusion gene containing only the NC1 domain was expressed under the control of the
let-2 promoter. The transgene weakly suppressed the DTC migration defects of
mig-17 mutants. These results suggest that the LET-2 type IV collagen functionally interacts with the MIG-17 ADAM protease and that the NC1 domain may play a key role in the mechanism of suppression.