Genetic interactions among ADAMTS metalloproteases and basement membrane molecules in cell migration in Caenorhabditis elegans.

Ayaka Imanishi,Yukihiko Kubota,Tomomi Takano,Hon-Song Kim,Yuma Aoki,Shunsuke Mori,Kiyoji Nishiwaki,Yukimasa Shibata,Masaki Kakehi,Myeongwoo Lee

doi:10.1371/journal.pone.0240571

Abstract

During development of the Caenorhabditis elegans gonad, the gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern to form the U-shaped gonad arms. The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloproteases MIG-17 and GON-1 are required for correct DTC migration. Mutations in mig-17 result in misshapen gonads due to the misdirected DTC migration, and mutations in gon-1 result in shortened and swollen gonads due to the premature termination of DTC migration. Although the phenotypes shown by mig-17 and gon-1 mutants are very different from one another, mutations that result in amino acid substitutions in the same basement membrane protein genes, emb-9/collagen IV α1, let-2/collagen IV α2 and fbl-1/fibulin-1, were identified as genetic suppressors of mig-17 and gon-1 mutants. To understand the roles shared by these two proteases, we examined the effects of the mig-17 suppressors on gon-1 and the effects of the gon-1 suppressors and enhancers on mig-17 gonadal defects. Some of the emb-9, let-2 and fbl-1 mutations suppressed both mig-17 and gon-1, whereas others acted only on mig-17 or gon-1. These results suggest that mig-17 and gon-1 have their specific functions as well as functions commonly shared between them for gonad formation. The levels of collagen IV accumulation in the DTC basement membrane were significantly higher in the gon-1 mutants as compared with wild type and were reduced to the wild-type levels when combined with suppressor mutations, but not with enhancer mutations, suggesting that the ability to reduce collagen IV levels is important for gon-1 suppression.

Highlights

Members of the ADAMTS family of secreted zinc metalloproteases have important roles in animal development
The U shape of the gonad arms are generated by migration of the gonadal leader cells, the distal tip cells (DTCs), over the body wall during larval development (Fig 1). gon-1 mutants exhibit shortened gonads due to the premature termination of DTC migration and are sterile
We identified alleles of emb-9 as mig-17 suppressors and an allele of let2 as a gon-1 suppressor for the first time

Summary

Introduction

Members of the ADAMTS family of secreted zinc metalloproteases have important roles in animal development. Most of these proteases degrade extracellular matrix components such as proteoglycans or collagens [1]. Nineteen ADAMTS genes have been identified in the human genome, and mutations in many of them result in hereditary diseases that are related to disorders of the extracellular matrix [2, 3]. Interaction among ADAMTS proteases and basement membrane proteins in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion