ABSTRACT
Discoidin domain receptors are a family of receptor tyrosine kinases activated by collagens. Here we characterize the role of the two discoidin domain receptors, ddr-1 and ddr-2, of the nematode C. elegans during nervous system development. ddr-2 mutant animals exhibit axon guidance defects in major longitudinal tracts most prominently in the ventral nerve cord. ddr-1 mutants show no significant phenotype on their own but significantly enhance guidance defects of ddr-2 in double mutants. ddr-1 and ddr-2 GFP-reporter constructs are expressed in neurons with axons in all affected nerve tracts. DDR-1 and DDR-2 GFP fusion proteins localize to axons. DDR-2 is required cell-autonomously in the PVPR neuron for the guidance of the PVPR pioneer axon, which establishes the left ventral nerve cord tract and serves as substrate for later outgrowing follower axons. Our results provide the first insight on discoidin domain receptor function in invertebrates and establish a novel role for discoidin domain receptors in axon navigation and axon tract formation.
Subject(s)
Axons/metabolism , Receptor Protein-Tyrosine Kinases/chemistry , Receptors, Mitogen/chemistry , Alleles , Animals , Axons/physiology , Cadherins/metabolism , Caenorhabditis elegans , Caenorhabditis elegans Proteins/metabolism , Collagen/chemistry , Discoidin Domain Receptors , Genes, Reporter , Membrane Glycoproteins/metabolism , Models, Biological , Mutation , Neurons/metabolism , Phenotype , Phylogeny , Protein Structure, Tertiary , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Mitogen/metabolism , TransgenesABSTRACT
BACKGROUND: Astacins are a large family of zinc metalloproteases found in bacteria and animals. They have diverse roles ranging from digestion of food to processing of extracellular matrix components. The C. elegans genome contains an unusually large number of astacins, of which the majority have not been functionally characterized yet. RESULTS: We analyzed the expression pattern of previously uncharacterized members of the astacin family to try and obtain clues to potential functions. Prominent sites of expression for many members of this family are the hypodermis, the alimentary system and several specialized cells including sensory sheath and sockets cells, which are located at openings in the body wall. We isolated mutants affecting representative members of the various subfamilies. Mutants in nas-5, nas-21 and nas-39 (the BMP-1/Tolloid homologue) are viable and have no apparent phenotypic defects. Mutants in nas-6 and nas-6; nas-7 double mutants are slow growing and have defects in the grinder of the pharynx, a cuticular structure important for food processing. CONCLUSIONS: Expression data and phenotypic characterization of selected family members suggest a diversity of functions for members of the astacin family in nematodes. In part this might be due to extracellular structures unique to nematodes.
Subject(s)
Caenorhabditis elegans/enzymology , Caenorhabditis elegans/genetics , Metalloendopeptidases/genetics , Metalloproteases/genetics , Animals , Caenorhabditis elegans/metabolism , PhylogenyABSTRACT
Two new chlorinated diphenyl ethers (5, 6) have been isolated from the culture broth of an Aspergillus species obtained from leaf litter, together with the known benzophenone sulochrin (1), the grisandiene geodin (2), and the diphenyl ether asterric acid (3). The structure of another metabolite, methyl asterrate (4), was confirmed by single-crystal X-ray structure analysis.
