Genetic Analyses of Dendrite Morphogenesis in Caenorhabditis Elegans

PI: Buelow, Hannes E. Project Summary Behavior in multicellular organisms is controlled by neural circuits in which neurons 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. 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, non-overlapping dendritic arbors that employ conserved mechanisms during dendrite morphogenesis. Previously, we have focused our studies on genes that are required for the formation of the dendritic arbors of PVD and FLP neurons, with a focus on non-autonomously acting factors. In this proposal, we will focus on two aspects that have been previously understudied, both with regard to PVD development, but also in general with regard to dendrite patterning. In genetic screens we have identified several loci that restrict branching. In Specific Aim 1, we will study loci we identified in genetic modifier screens of a hypomorphic allele of the KPC-1/Furin proprotein convertase. We had previously found that KPC- 1/Furin functions cell-autonomously in PVD neurons to negatively regulate dendritic branching. This aim is designed to elucidate the molecular mechanisms by which KPC-1/Furin restricts branching. In addition, we will study an allele that constitutes a mutation in a transcription factor binding site of a gene encoding an actin regulatory protein. In Specific Aim 2, we will focus on a putative rab-related GTPase, which we have found to function in the epidermis to restrict dendrite branching. This aim is focused on determining the mechanisms by which this putative GTPase controls branching non- autonomously from the skin. In addition, we will study an allele that displays the same phenotype as a mutant in the GTPase to gain additional insight into the process of how branching is restricted. Finally, The FLP and PVD neurons provide a unique opportunity to study the processes of heterotypic tiling (i.e. the tiling of receptive fields between two different types of neurons) and the control of dendritic field size in molecular detail. In a combination of forward and candidate genetic screens we have identified a number of genes that regulate tiling between FLP and PVD dendrites. Therefore, in Specific Aim 3, we will determine the genetic and molecular mechanisms that govern heterotypic tiling and the control of field size. In summary, this proposal is aimed at understanding the molecular and genetic mechanisms that restrict and control dendritic branching on the one hand and, the processes that ensure establishment of non-overlapping dendritic fields of defined size between different types of neurons.