Functions of the SLC36 transporter Pathetic in growth control of Drosophila sensory neurons

Thesis (Ph.D.)--University of Washington, 2016-08

Dendrites exhibit enormous diversity in form and can differ in size by several orders of magnitude even in a single animal. However, whether neurons with large dendrite arbors have specialized mechanisms to support their growth demands is unknown. To address this question, we conducted a genetic screen for mutations that differentially affected growth in neurons with different sized dendrite arbors. From this screen, we identified a mutant that selectively affects dendrite growth in neurons with large dendrite arbors without affecting dendrite growth in neurons with small dendrite arbors or the animal overall. This mutant disrupts a putative amino acid transporter, Pathetic (Path), that localizes to the cell surface and endolysosomal compartments in neurons. Although Path is broadly expressed in neurons and non-neuronal cells, mutation of path impinges on nutrient responses and protein homeostasis specifically in neurons with large dendrite arbors, but not in other cells. To gain insight into the basis of growth control by path, we generated additional alleles of path and further examined the apparent specificity of growth defects in path mutants. We confirm our prior finding that loss of path function imposes an upper limit on neuron growth, and additionally report that path likely limits overall neurite length rather than dendrite length alone. Besides this, path mutant affects presynapse formation in C4da axons and nociceptive escape response. Using a GFP knock-in allele of path, we identify additional tissues where path likely functions in nutrient sensing and possibly growth control. Moreover, we demonstrate that path regulates translational capacity in a cell type that does not normally require path for growth, suggesting that path may confer robustness on growth programs by buffering translational output. Finally, we discovered that path mutant has dramatically shortened life span, but neuronal Path or path expression in other tissues can partially rescue the path mutant life span. Altogether, our results demonstrate that specialized molecular mechanisms exist to support growth demands in neurons with large dendrite arbors and define Path as a founding member of this growth program. Moreover, Path is a nutrient sensor with widespread function in Drosophila.