The migration of Caenorhabditis elegans gonadal distal tip cells (DTCs) offers an excellent model to study the migration of epithelial tubes in organogenesis. mig-18 mutants cause meandering or wandering migration of DTCs during gonad formation, which is very similar to that observed in animals with mutations in mig-17, which encodes a secreted metalloprotease of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family. MIG-18 is a novel secreted protein that is conserved only among nematode species. The mig-17(null) and mig-18 double mutants exhibited phenotypes similar to those in mig-17(null) single mutants. In addition, the mutations in fbl-1/fibulin-1 and let-2/collagen IV that suppress mig-17 mutations also suppressed the mig-18 mutation, suggesting that mig-18 and mig-17 function in a common genetic pathway. The Venus-MIG-18 fusion protein was secreted from muscle cells and localized to the gonadal basement membrane, a tissue distribution reminiscent of that observed for MIG-17. Overexpression of MIG-18 in mig-17 mutants and vice versa partially rescued the relevant DTC migration defects, suggesting that MIG-18 and MIG-17 act cooperatively rather than sequentially. We propose that MIG-18 may be a cofactor of MIG-17/ADAMTS that functions in the regulation of the gonadal basement membrane to achieve proper direction of DTC migration during gonadogenesis.T HE ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family of the secreted zinc metalloproteases has important roles in development. Nineteen ADAMTS genes have been identified in the human genome, and mutations in many result in hereditary diseases that are related to disorders of the extracellular matrix (Apte 2009). The functions of ADAMTS-5, -9, and -20 are required for digit formation, and ADAMTS-9 and -20 are needed for closure of the palate in mice (McCulloch et al. 2009;Enomoto et al. 2010). ADAMTS-5 and -15 act in myoblast fusion (Stupka et al. 2013). However, the precise roles of ADAMTS proteases in development still remain elusive.Among five ADAMTS genes in Caenorhabditis elegans, gon-1 and mig-17 play essential roles in the development of the somatic gonad (Blelloch and Kimble 1999;Nishiwaki et al. 2000). GON-1 is required for active migration of gonadal distal tip cells (DTCs), whereas MIG-17 acts in the directional control of DTC migration. Genetic suppressor analyses of mig-17 mutants identified dominant gain-of-function (gf) mutations in two genes that encode basement membrane proteins, FBL-1C/ fibulin-1C and LET-2/a2 subunit of collagen IV (Kubota et al. 2004(Kubota et al. , 2008. The suppressor fbl-1(gf) mutations result in substitutions of evolutionarily conserved amino acids within the second EGF-like motif of FBL-1C. FBL-1C is recruited to the gonadal basement membrane by MIG-17 activity, where it is likely to be required for directional control of DTC migration (Kubota et al. 2004). The suppression by fbl-1(gf) mutations depends on NID-1/nidogen, a basement membrane protein et al. ...
Organs are often formed by the extension and branching of epithelial tubes. An appropriate termination of epithelial tube extension is important for generating organs of the proper size and morphology. However, the mechanism by which epithelial tubes terminate their extension is mostly unknown. Here we show that the BED-finger domain protein MIG-39 acts to stop epithelial tube extension in Caenorhabditis elegans. The gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern during larval development and stop migrating at the young adult stage, generating a gonad with anterior and posterior U-shaped arms. In mig-39 mutants, however, DTCs overshot their normal stopping position. MIG-39 promoted the deceleration of DTCs, leading to the proper timing and positioning of the cessation of DTC migration. Among three Rac GTPase genes, mutations in ced-10 and rac-2 enhanced the overshoot of anterior DTCs, while they suppressed that of posterior DTCs of mig-39 mutants. On the other hand, the mutation in mig-2 suppressed both the anterior and posterior DTC defects of mig-39. Genetic analyses suggested that MIG-39 acts in parallel with Rac GTPases in stopping DTC migration. We propose a model in which the anterior and posterior DTCs respond in an opposite manner to the levels of Rac activities in the cessation of DTC migration.
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