The transmembrane collagen col-99 and the collagen receptors ddr-1 and ddr-2 regulate axon guidance in caenorhabditis elegans

During development, neurons extend axons over long distances to connect to their target cells. Growth cones, specialized structures at the tip of extending axons interact with a vast number of extracellular cues en route to their target. These guidance cues are detected by specific receptors expressed on the growth cone. Receptor-ligand binding triggers downstream signaling pathways that affect actin and microtubule assembly in the growth cone leading to directed outgrowth. The identification of these guidance cues and their corresponding receptors is essential for our understanding of the molecular mechanisms underlying neuronal connectivity. The aim of this study was the identification and characterization of novel genes involved in axon guidance in the nematode Caenorhabditis elegans. We have identified the laminin αB subunit EPI-1, the two collagen receptors DDR-1 and DDR-2 and their potential ligand collagen COL-99. DDR-1 and DDR-2 are the two C. elegans homologs of the receptor tyrosine kinase family of discoidin domain receptors. COL-99 represents a novel transmembrane collagen with similarity to collagen XIII and XXV in vertebrates. Mutants in col-99 exhibited axon guidance defects in the major longitudinal nerve tracts, most prominently in the left ventral nerve cord. Analysis of the ddr-2 mutant phenotype revealed similar but less penetrant defects in these axon tracts. We found that DDR-2 functions cell-autonomously in the primary axon establishing the left ventral nerve cord. ddr-1 mutants showed no significant phenotype on their own but significantly enhanced guidance defects of ddr-2 in double mutants. Both genes interacted genetically with col-99 and were expressed in the neurons projecting in the nerve tracts affected in col-99 mutants. The DDR-1 and DDR-2 proteins localized to axons. COL-99 was expressed on the cell surface of hypodermal cells underlying the future nerve tracts and might serve as ligand for DDR-1 and DDR-2 expressing growth cones during axonal outgrowth in the embryo.