PI: Buelow, Hannes E. Project Summary Behavior in multicellular organisms is controlled by neural circuits, which consist of interconnected neurons that integrate synaptic input, and compute output. Most neurons are bipolar and comprise dendrites and axons, which mediate reception and transmission of information, respectively. Dendrite branching is necessary for correct circuit assembly. While great strides have been made to understand axon development and branching, less is known about dendrite development. We are using the pair of PVD and FLP neurons in the small nematode C. elegans to investigate basic genetic and molecular mechanisms of dendrite development. Both PVD and FLP neurons elaborate highly branched dendritic arbors that employ conserved mechanisms during dendrite development. In a genetic screen for loci required for the formation of the stereotypic dendritic arbors of PVD neurons, we retrieved mutants with defects in PVD dendrite morphogenesis. Analyses of several of these genes identified the `menorin' pathway. This pathway is comprised of the conserved novel cell adhesion molecule MNR-1/menorin that acts in a complex with the adhesion molecule SAX-7/L1CAM from the skin through a leucine rich transmembrane receptor on PVD dendrites. In addition, we have found that the proprotein convertase kpc-1/furin acts genetically in the menorin pathway and that catalytic activity is required in PVD for patterning different aspects of dendritic arbor development. This proposal is aimed at two basic questions that arise from our published and unpublished studies. First, what are the in vivo targets of the proprotein convertase KPC-1/furin during these processes? Second, what may be the signaling pathway(s) operating within the PVD (or FLP) neurons? In the first aim we will define and characterize in vivo targets of the proprotein convertase kpc-1/furin that we have identified by a combination of proteomics and a candidate gene approach. In a second aim we will analyze the function of a novel extracellular protein, which has not previously been implicated in PVD dendrite development and which also appears to act in the `menorin' pathway. In a third aim, we will conduct a phenotypic, genetic and molecular characterization of an intracellular signaling molecule, which acts in PVD within the menorin pathway and likely downstream of the DMA-1 transmembrane receptor. In sum, our studies are aimed at a better understanding of basic aspects of dendrite development by focusing on non-autonomous mechanisms that in conjunction with a novel pathway pattern development of somatosensory dendrites.